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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                     CARDIOVASCULAR AND RENAL DRUGS

 

                           ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                           September 10, 2004

 

                               8:31 a.m.

 

 

 

 

 

 

 

                              Holiday Inn

                          Versailles Ballrooms

                           Bethesda, Maryland

                                                                 2

 

                        P A R T I C I P A N T S

 

      Dornette Spell-LeSane, M.H.A., NP-C, Executive

      Secretary

 

      Jeffrey S. Borer, M.D., Acting Chairman

      Steve Nissen, M.D.

      Alan T. Hirsch, M.D.

      Thomas Fleming, Ph.D.

      Maria H. Sjogren, M.D.

      Jonathan Sackner-Bernstein, M.D.

      John R. Teerlink M.D.

 

      Susanna L. Cunningham, Ph.D.

      William R. Hiatt, M.D.

      Beverly H. Lorell, M.D.

      Thomas Pickering, M.D.

      Ronald Portman, M.D.

 

      Paul Watkins, M.D., Ph.D.

      Jose Vega, M.D.

 

      FDA Participants

 

      Dr. Mark Avigan

      Dr. Florence Houn

      Dr. Joyce Korvick

      Dr. Kathy Robie-Suh

                                                                 3

 

                            C O N T E N T S

 

      AGENDA ITEM                                             PAGE

 

      Call to Order and Introductions - Jeffrey S. Borer,

      M.D., Acting Chair                                         5

 

      Conflict of Interest Statement - Dornette

      Spell-LeSane, NP-C, Executive Secretary                    8

 

      Welcome and Comments - Norman Stockbridge, M.D.,

      Acting Director, Division of Cardiovascular and

      Renal Drug Products, FDA                                  13

 

      Sponsor Presentation

 

      Introduction - Hamish Cameron, M.D., Vice

      President, Exanta                                         15

 

      Clinical Pharmacology - Troy Sarich, Ph.D.,

      Director, Clinical Pharmacology                           24

 

      Efficacy - Jay Horrow, M.D., Senior Director,

      Clinical Development                                      43

 

      Safety - Sunita Sheth, M.D., Senior Director,

      Clinical Development                                      97

 

      Benefit and Risk Anticoagulation - Jonathan L.

      Halperin, M.D., Mount Sinai Medical Center, New

      York                                                     163

 

      FDA Presentation

 

      Risk/Benefit Assessment - Ruyi He, M.D., Medical

      Officer, Division of Gastrointestinal and

      Coagulation Drug Products                                172

 

      Risk Management of Hepatotoxic Drugs - Kate

      Gelperin, M.D., M.P.H., Medical Epidemiologist,

      Division of Drug Risk Evaluation                         282

 

      Drug-Induced Liver Toxicity - Paul Watkins, M.D.,

      Verne S. Caviness Distinguished Professor of

      Medicine, Director, General Clinical Research

      Center, University of North Carolina

      Medical Center                                           301

                                                                 4

 

                      C O N T E N T S (Continued)

 

      AGENDA ITEM                                             PAGE

 

      Questions from the Committee                              --

 

      Open Public Hearing                                      184

 

      Charge to the Committee - Joyce Korvick, M.D.,

      M.P.H., Acting Division Director, Division of

      Gastrointestinal and Coagulation Drug Products, FDA      318

 

      Committee Discussion                                     319

 

      Break                                                     --

 

      Committee Questions/Summary                              320

 

      Adjournment                                              414

 

                                                                 5

 

                         P R O C E E D I N G S

 

                DR. BORER:  It's 8:30 and I'm going to

 

      call the meeting to order.  This is the Cardiovascular and

 

      Renal Drugs Advisory Committee

 

      meeting, and we will discuss New Drug Application

 

      (NDA) 21-686, proposed trade name Exanta

 

      (ximelagatran) by AstraZeneca, for the proposed

 

      indication of the prevention of venous thromboembolism in

 

      patients undergoing knee replacement

 

      surgery, the prevention of stroke and other

 

      thromboembolic complications associated with atrial

 

      fibrillation, and the long-term secondary

 

      prevention of venous thromboembolic events after

 

      standard treatment following an episode of acute

 

      venous thromboembolic event.

 

                We'll begin by introducing everybody at

 

      the table.  In this meeting, the Cardio/Renal

 

      Committee actually is advising the GI Division as

 

      well as Cardio/Renal, in fact, primarily the GI

 

      Division, so we have more people at the table than

 

      we sometimes do.  Maybe we can each say our name

 

      and what we're doing here, and we'll start with Dr.

 

                                                                 6

 

      Vega on the far side.

 

                DR. VEGA:  I'm Jose Vega.  I'm the

 

      industry representative on the committee, and I'm

 

      from Amgen.

 

                DR. PICKERING:  Tom Pickering from

 

      Columbia Presbyterian Hospital in New York.

 

                DR. PORTMAN:  Ron Portman from the

 

      University of Texas in Houston.

 

                DR. HIATT:  Bill Hiatt, University of

 

      Colorado.

 

                DR. LORELL:  Bev Lorell, Harvard Medical

 

      School, and also Guidant Corporation.

 

                DR. SACKNER-BERNSTEIN:  Jonathan

 

      Sackner-Bernstein, North Shore University Hospital

 

      in New York.

 

                DR. CUNNINGHAM:  Susanna Cunningham.  I am

 

      the consumer representative on the committee, and

 

      I'm from the University of Washington.

 

                DR. NISSEN:  I'm Steve Nissen.  I'm a

 

      cardiologist at the Cleveland Clinic.

 

                DR. WATKINS:  Paul Watkins.  I'm a

 

      hepatology consultant from University of North

 

                                                                 7

 

      Carolina-Chapel Hill.

 

                DR. BORER:  Jeff Borer, cardiologist,

 

      Weill Medical College of Cornell University.

 

                MS. SPELL-LeSANE:  Dornette Spell-LeSane,

 

      Executive Secretary for the committee.

 

                DR. TEERLINK:  John Teerlink, University

 

      of California-San Francisco, and San Francisco VA

 

      Medical Center.

 

                DR. FLEMING:  Tom Fleming, University of

 

      Washington.

 

                DR. HIRSCH:  Alan Hirsch, cardiologist and

 

      vascular medicine specialist at the University of

 

      Minnesota and Minneapolis Heart Institute.

 

                DR. AVIGAN:  Mark Avigan, Office of Drug

 

      Safety at the FDA.

 

                DR. STOCKBRIDGE: I'm Norman Stockbridge,

 

      the Acting Director of the Division of Cardio/Renal

 

      Drug Products at FDA.

 

                DR. HOUN:  I'm Florence Houn.  I'm the

 

      Office Director for Drug Evaluation III.

 

                DR. KORVICK:  Joyce Korvick, Acting

 

      Director, Division of Gastrointestinal Coagulation

 

                                                                 8

 

      Drug Products.

 

                DR. ROBIE-SUH:  Kathy Robie-Suh, Acting

 

      Deputy Director, Division of Gastrointestinal and

 

      Coagulation Drug Products.

 

                DR. BORER:  Thank you very much.

 

                We have many people at the table.  I'm

 

      going to remind everyone that when you speak, you

 

      should press the button on your microphone, and

 

      when you're done, turn it off, please, unless you

 

      want to say something because that's the only way

 

      I'm going to know that you want to if you press the

 

      button and I see the light.

 

                We'll go on to the conflict of interest

 

      statement.  Dornette Spell-LeSane, the Executive

 

      Secretary of the Cardio/Renal Drug Advisory

 

      Committee, will present the conflict of interest.

 

                MS. SPELL-LeSANE:  Good morning.  The

 

      following announcement addresses the issue of

 

      conflict of interest and is made part of the record

 

      to preclude even the appearance of such at this

 

      meeting.  Based on the submitted agenda and all

 

      financial interests reported by the committee

 

                                                                 9

 

      participants, it has been determined that all

 

      interests in firms regulated by the Center for Drug

 

      Evaluation and Research present no potential for an

 

      appearance of a conflict of interest at this

 

      meeting, with the following exceptions:

 

                In accordance with 18 U.S.C. Section

 

      208(b)(3), full waivers have been granted to the

 

      following participants.  Please note that all of

 

      the consulting and speaking activities waived are

 

      unrelated to Exanta and its competing products:

 

                Dr. William Hiatt for consulting for two

 

      competitors for which he receives less than $10,001

 

      per year per firm;

 

                Dr. Thomas Pickering for serving on a

 

      competitor's advisory board for which he receives

 

      less than $10,001 per year;

 

                Dr. Ronald Portman for consulting for a

 

      competitor for which he receives less than $10,001

 

      per year;

 

                Dr. Thomas Fleming for consulting for four

 

      competitors, he receives less than $10,001 per year

 

      per firm;

 

                                                                10

 

                Dr. Sackner-Bernstein for consulting for

 

      the sponsor and a competing firm, he receives less

 

      than $10,001 per year per firm.  Also, for his

 

      Speaker Bureau activities for a competitor, he

 

      receives less than $10,001 to $50,000 per year;

 

                Dr. Jeffrey Borer for serving on a

 

      steering committee for a competitor, he receives

 

      less than $10,001 per year;

 

                Dr. Alan Hirsch for lecturing for the

 

      sponsor, for which he receives less than $5,001 per

 

      year.  For lecturing for three competing firms, he

 

      receives less than $5,001 per year for serving on

 

      two Speaker Bureaus, and from $5,001 to $10,001 for

 

      one Speakers Bureau.  Two consulting agreements for

 

      two competing firms, he receives less than $10,001

 

      per year for one consulting, and from $10,001 to

 

      $50,000 per year for the other.

 

                In accordance with 18 U.S.C. 208(b)(3), a

 

      limited waiver has been granted to Dr. Paul Watkins

 

      for serving on two advisory boards for a competing

 

      firm.  He receives less than $10,001 per year for

 

      one and greater than $50,000 per year for the

 

                                                                11

 

      other.  Under the terms of this limited waiver, Dr.

 

      Watkins will be permitted to participate in the

 

      committee's discussion of Exanta.  He is, however,

 

      excluded from voting.

 

                Lastly, in accordance with 18 U.S.C.

 

      Section 208(b)(1), full waivers have been granted

 

      to the following participants for interests

 

      unrelated to Exanta and its competing products:

 

                Dr. John Teerlink for speaking for two

 

      competitors, he receives less than $10,001 per year

 

      from one, and from $10,001 to $50,000 per year from

 

      the other.  Also, for his consulting for a

 

      competitor for which he receives between $10,000 to

 

      $50,000 per year;

 

                Dr. Maria Sjogren for consulting for a

 

      competitor for which she receives less than $10,001

 

      per year.

 

                A copy of the waiver statement may be

 

      obtained by submitting a written request to the

 

      agency's Freedom of Information Office, Room 12A-30

 

      of the Parklawn Building.  In the event that the

 

      discussions involve any other products or firms not

 

                                                                12

 

      already on the agenda for which FDA participants

 

      have a financial interest, the participants are

 

      aware of the need to exclude themselves from such

 

      involvement, and their exclusion will be noted for

 

      the record.

 

                We would also like to note that Dr. Jose

 

      Vega has been invited to participate as an industry

 

      representative acting on behalf of regulated

 

      industry.  Dr. Vega is employed by Amgen.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose products they may wish to comment

 

      upon.

 

                Thank you.

 

                DR. BORER:  Thank you very much, Dornette.

 

      That was about the longest conflict of interest

 

      statement that I can remember.

 

                But we still are five minutes ahead,

 

      Norman, so we'll hear a welcome and comments from

 

      Norman Stockbridge, the Acting Director of the

 

      Division of Cardiovascular and Renal Drug Products.

 

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                DR. STOCKBRIDGE:  I'll see if I can keep

 

      us on schedule.  Good morning and welcome to what

 

      promises to be an interesting meeting on behalf of

 

      the Divisions of Cardio/Renal Drug Products and GI

 

      and Coagulation Drug Products.  I want to thank

 

      members of the Cardio/Renal Advisory Committee,

 

      consultants, and the sponsor for their

 

      participation.

 

                I do need to acknowledge retirement of

 

      four members from the Advisory Committee:  Alan

 

      Hirsch is here today, a couple of chairs down to my

 

      left; Steve Nissen is over at the middle of the

 

      table there; Paul Armstrong would be here today

 

      except that Homeland Security discovered that he's

 

      a Canadian.

 

                [Laughter.]

 

                DR. STOCKBRIDGE:  And, finally, there is

 

      our Chairman, Dr. Jeff Borer.  Dr. Borer's service

 

      to the committee began in 1977, an era in which

 

      members still sported powdered wigs.

 

                [Laughter.]

 

                DR. STOCKBRIDGE:  I can't quite tell from

 

                                                                14

 

      the records where he cast his first vote, but in

 

      that year, the committee heard arguments on

 

      potassium and atropine.

 

                As tokens of our appreciation, Ms.

 

      Spell-LeSane has for each of you some actual

 

      certificates signed by our Acting Commissioner and

 

      some virtual plaques that look just like this one.

 

      So on behalf of Cardio/Renal, the Food and Drug

 

      Administration, and a grateful nation, thanks to

 

      you all.

 

                [Applause.]

 

                DR. NISSEN:  Norman, I'm not from Canada,

 

      but I'm from Cleveland, and it's really close to

 

      Canada.  Will you please not tell Homeland Security

 

      about me?

 

                DR. BORER:  Thank you very much, Norman,

 

      and thank you for staying way on time because we

 

      are now 17 minutes ahead of schedule, which is

 

      good.  The sponsor has a 90-minute presentation.

 

      We'll try to allow you to move along as well as we

 

      can, but undoubtedly there will be some clarification

 

      questions.  We ought to try to hold the

 

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      questions that we ask to clarification issues

 

      during the presentation, if we can, and we can get

 

      into the meat of the substantive discussion

 

      afterwards.

 

                The presentation will be introduced by Dr.

 

      Cameron, the Vice President of Exanta.

 

                DR. CAMERON:  Thank you, Mr. Chairman,

 

      members of the committee, ladies and gentlemen,

 

      good morning.  I'm Dr. Hamish Cameron, the Vice

 

      President of Exanta at AstraZeneca, and with my

 

      colleagues we're pleased to present ximelagatran, a

 

      new oral anticoagulant.

 

                After a 20-year journey to discover and

 

      develop this new medicine and half a century

 

      without significant innovation in this area of

 

      therapeutics, we believe ximelagatran, the first

 

      oral treatment in the new drug class direct

 

      thrombin inhibitors is a real advance in oral

 

      anticoagulation.

 

                Ximelagatran has a mechanism of action

 

      that's quite different from the vitamin K

 

      antagonists like warfarin and can provide the first

 

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      oral alternative to warfarin, today's only option

 

      for long-term anticoagulation.

 

                Anticoagulation is the major approach to

 

      both the prevention and treatment of thromboembolic

 

      disease, a disease that's the final common pathway

 

      for many life-threatening conditions, like stroke,

 

      myocardial infarction, and pulmonary embolism.  And

 

      it's the commonest cause of death and disability in

 

      America today.

 

                At the outset we must ask:  Given the

 

      widespread availability of the vitamin K

 

      antagonists like warfarin, why is there a need for

 

      a new oral anticoagulant?  Warfarin is a highly

 

      efficacious anticoagulant and one of the top ten

 

      most prescribed drugs, used in nearly every medical

 

      specialty by 3 million patients in the U.S.

 

      involving 32 million prescriptions every year.  But

 

      it's been in the top five, sometimes number one, in

 

      the lists of drugs associated with significant

 

      interactions, medication errors, serious bleeding,

 

      and hospital admissions.

 

                Warfarin's profile of unpredictable

 

                                                                17

 

      kinetics and dynamics; food, alcohol, and multiple

 

      drug interactions; together with its acknowledged

 

      narrow therapeutic index--too little warfarin, and

 

      there's the risk of residual clotting; too much,

 

      and the risk of bleeding--all these drive the need

 

      for a lifetime of INR coagulation monitoring and

 

      never-ending individual dose titration.

 

                To put it simply, you don't get the

 

      benefit of warfarin from just taking the tablet.

 

      Its overall effectiveness is highly dependent on

 

      how it's managed.  And it's this fact that frames

 

      the innovation of ximelagatran.

 

                Many patients and doctors fear the risk of

 

      bleeding that comes with unpredictable anticoagulation.

 

      This fear tends to result in

 

      under-treatment, quite paradoxical in high-risk

 

      elderly patients, or in about half the overall

 

      patients eligible for warfarin, little or no

 

      treatment at all.

 

                We started a discovery program targeting

 

      thrombin in 1985.  We sought to develop a new oral

 

      anticoagulant, an alternative to warfarin, with a

 

                                                                18

 

      profile that would allow fixed dosing without

 

      coagulation monitoring, further supported by a low

 

      potential for food and drug interactions.

 

                We looked for a rapid onset and offset of

 

      action to simplify turning anticoagulation on and

 

      off, which is one of the challenging aspects of

 

      warfarin treatment.  And all this had to be

 

      achieved with an acceptable bleeding profile.

 

                Today, we believe these objectives have

 

      been met by the Ximelagatran Development Program,

 

      involving 82 clinical studies and enrolling over

 

      30,000 subjects.  More than 17,000 people received

 

      ximelagatran with 3,500 patients dosed for over a

 

      year.  And our longest patient exposure has now

 

      reached five years.

 

                Here are the three proposed indications in

 

      the current NDA, spanning exposures from days to

 

      several years.  The first is the long-term

 

      secondary prevention of venous thromboembolism,

 

      VTE, after standard treatment for an acute episode.

 

      Treatment of acute VTE involved six months of

 

      anticoagulation with warfarin, but at the start of

 

                                                                19

 

      this development in 1999, it was unknown whether

 

      longer treatment would be beneficial.  And so a

 

      placebo-controlled study, THRIVE III, was

 

      conducted.  As you'll see, this study demonstrated

 

      a highly significant reduction of VTE during

 

      longer-term prophylactic treatment.  And as a

 

      placebo-controlled study, it provides the strongest

 

      evidence of ximelagatran's antithrombotic efficacy.

 

                The second indication is the prevention of

 

      VTE after knee replacement surgery.  Patients

 

      without anticoagulant prophylaxis run a high risk

 

      of DVT and pulmonary embolism, and in the U.S.,

 

      warfarin is the most widely used drug, started late

 

      on the day of surgery to reduce this risk.  In two

 

      warfarin controlled studies, EXULT A and EXULT B,

 

      we've shown a significant reduction of VTE risk for

 

      ximelagatran compared with warfarin.

 

                The third indication is the prevention of

 

      stroke and other thromboembolic complications

 

      associated with atrial fibrillation.  Here with the

 

      large SPORTIF III and V trials, we've shown the

 

      efficacy of ximelagatran to be comparable to

 

                                                                20

 

      well-controlled warfarin.

 

                Across these pivotal, mainly

 

      outcomes-based studies involving independent

 

      endpoint adjudication, we've demonstrated

 

      ximelagatran's antithrombotic efficacy and recorded

 

      a favorable leading profile, equivalent to and in

 

      some cases better than the comparator.  We detected

 

      a signal of raised hepatic enzymes with chronic

 

      treatment, and so we've conducted a very detailed

 

      analysis, consulted with experts, and believe the

 

      risk can be adequately managed.

 

                I should highlight that in your briefing

 

      packs and our safety presentation, we've included

 

      data from two other large studies in other

 

      indications, not for consideration today, but which

 

      contribute nearly 4,000 patients.  The THRIVE

 

      treatment study is the first pivotal study looking

 

      at initial VTE treatment, and the second study is

 

      soon to start, while the ESTEEM trial is a Phase II

 

      dose guiding study in the post-acute coronary

 

      syndrome setting.

 

                These data enrich the overall safety

 

                                                                21

 

      assessment, including patients from very different

 

      clinical settings and a wide range of characteristics, and

 

      we're going to review all the key

 

      data in the presentations that follow.

 

                We believe ximelagatran with its

 

      predictable anticoagulant effects and favorable

 

      bleeding profile has a positive benefit/risk in the

 

      proposed indications, provided it's used properly.

 

      And part of that proper use is the introduction of

 

      an appropriate risk management program directed

 

      towards the hepatic risk.

 

                We made an initial proposal with our

 

      submission which had been developed with extensive

 

      external consultation and field testing, but we

 

      fully recognize, following the deliberations of

 

      this committee and further discussions with FDA,

 

      the program will need to be developed and

 

      strengthened further before an approach can be

 

      finalized in the best interests of patients.  We

 

      are committed to working with FDA to achieve the

 

      most appropriate risk management program to ensure

 

      the safe use of ximelagatran because patient safety

 

                                                                22

 

      is, has been, and always will be AstraZeneca's top

 

      priority when we introduce new medicines into

 

      clinical practice.

 

                Since 1998, we've met repeatedly with FDA

 

      throughout ximelagatran's development--in end of

 

      Phase II meetings, a pre-NDA interaction, and

 

      there's a meeting coming up to discuss the nature

 

      and extent of the risk management program.  The NDA

 

      was submitted in December 2003.

 

                I should add that all the same data are

 

      now being reviewed in Europe by the French agency

 

      before a mutual recognition procedure.  But there's

 

      one difference worth noting.  Given the quite

 

      different clinical practice regarding anticoagulant

 

      prophylaxis in orthopedic surgery, separate

 

      developments were conducted in the U.S. and Europe.

 

      The European program, reflecting local practice and

 

      starting treatment much closer to the time of

 

      operation, was the subject of a separate earlier

 

      regulatory submission and completed the mutual

 

      recognition procedure in May this year.  And the

 

      first orthopedic launch was in Germany in June.

 

                                                                23

 

                Now, you have the data on this program in

 

      your briefing packs, but with the significant

 

      timing, comparator, and formulation differences,

 

      our presentations today will largely focus on the

 

      data directly relevant to the NDA orthopedic

 

      surgery application.

 

                Here's the agenda for our session.  Dr.

 

      Troy Sarich will review clinical pharmacology; Dr.

 

      Jay Horrow, efficacy; and Dr. Sunita Sheth, safety;

 

      allowing an overall evaluation of ximelagatran in

 

      the three requested indications.  Dr. Jonathan

 

      Halperin from Mount Sinai Medical Center will then

 

      give his views on the benefit/risk of ximelagatran

 

      in clinical practice.  And throughout our

 

      presentations, we hope to cover for you all the

 

      specific comments raised by the agency in their

 

      briefing document.

 

                In addition to Dr. Halperin, we're also

 

      joined by other consultants:  Dr. Gerald Faich, Dr.

 

      Lloyd Fisher, Dr. Peter Kowey, and Dr. James Lewis.

 

                In summary, then, ximelagatran is a new

 

      oral anticoagulant that provides the first

 

                                                                24

 

      alternative to warfarin after 50 years.  We believe

 

      a total review of the available clinical data

 

      supports a positive benefit/risk in each of the

 

      proposed indications.  Ximelagatran can enhance

 

      health care delivery in America and throughout the

 

      world to help prevent a range of debilitating and

 

      life-threatening thromboembolic diseases.

 

                Thank you.  Now I'd like to introduce Dr.

 

      Troy Sarich for clinical pharmacology.

 

                DR. SARICH:  Good morning.  I'm Dr. Troy

 

      Sarich, Director of Clinical Pharmacology at

 

      AstraZeneca.  I'll now present an overview of the

 

      clinical pharmacology of ximelagatran in which we

 

      have performed both the traditional clinical

 

      pharmacology studies and population pharmacokinetic

 

      analyses.

 

                Ximelagatran is an oral direct thrombin

 

      inhibitor.  It's rapidly bioconverted to the active

 

      form, melagatran.  The bioconversion, which is

 

      Cytochrome P-450 independent, involves both

 

      de-esterification and a reduction that occurs

 

      throughout the body.

 

                                                                25

 

                The exposure to melagatran is linear

 

      across a dose range from 5 to 98 milligrams

 

      ximelagatran.  The pharmacokinetics are predictable

 

      over time with repeated dosing, and the elimination

 

      half-life of melagatran is approximately 4 to 5

 

      hours in patients.  Once formed, melagatran is

 

      primarily eliminated from plasma by a glomerular

 

      filtration.

 

                Thrombin is a key enzyme in the

 

      coagulation cascade.  It converts fibrinogen to

 

      fibrin, activates platelets, and induces its own

 

      generation.  Melagatran directly inhibits thrombin

 

      as a classic competitive and reversible-binding

 

      enzyme inhibitor.  There's a direct relationship

 

      between the pharmacokinetics and pharmacodynamics

 

      of ximelagatran.  Its active when present in

 

      plasma, and once eliminated from plasma, its effect

 

      is gone.

 

                Preclinical investigations indicated an

 

      antithrombotic effect of melagatran at approximately 0.05

 

      micromolar, with increasing effect up

 

      to approximately 0.5 micromolar.

 

                                                                26

 

                In humans, ximelagatran prolongs clotting

 

      time assays.  The thrombin time assay shown here

 

      was prolonged in a linear manner at concentrations

 

      as low as 0.05 micromolar.  In addition, melagatran

 

      prolongs in a concentration-dependent manner the

 

      activated partial thromboplastin time, although it

 

      is less sensitive.

 

                Additional investigations using

 

      pharmacodynamic models in humans demonstrated

 

      evidence for inhibition of thrombin generation

 

      indicated by concentration-dependent reduction and

 

      thrombin-antithrombin complex levels and platelet

 

      activation indicated by concentration-dependent

 

      reduction in beta thromboglobulin levels at

 

      melagatran concentrations at or near 0.05

 

      micromolar.  All together, it was clear from these

 

      data that direct inhibition of thrombin by

 

      melagatran resulted in the intended anticoagulant

 

      activity in humans.

 

                After oral administration, the inactive

 

      pro drug ximelagatran is rapidly eliminated from

 

      plasma as it is biotransformed to melagatran, shown

 

                                                                27

 

      in blue, with peak melagatran concentrations

 

      occurring approximately 2 to 3 hours post-dosing.

 

      Melagatran plasma concentrations greater than 0.05

 

      micromolar are achieved early after oral ximelagatran,

 

      indicating a rapid onset of action which

 

      simplifies the initiation of oral anticoagulation.

 

      Concentrations remain above 0.05 micromolar

 

      throughout the dosing interval, supporting a

 

      twice-daily dosing regimen.

 

                And as shown here, the rapid onset of

 

      action of oral ximelagatran is not altered when

 

      co-administered with food.  Although there's an

 

      approximately one-hour delay in the time to C-max,

 

      there is no effect on the AUC or Cmax of

 

      melagatran.

 

                Warfarin's well-recognized drug

 

      interaction profile is largely related to its

 

      metabolism by the Cytochrome P-450 system and its

 

      high plasma protein binding.  Ximelagatran is not

 

      metabolized by and does not inhibit the major

 

      Cytochrome P-450 enzymes listed here.  It also has

 

      low plasma protein binding, and along with the

 

                                                                28

 

      majority of melagatran eliminated from plasma by

 

      glomerular filtration, this leads to an inherently

 

      low potential for drug interactions.

 

                Our investigations have identified

 

      pharmacokinetic interactions with erythromycin and

 

      azithromycin.  Erythromycin results in an

 

      80-percent or less than twofold increase in

 

      melagatran plasma levels, with a smaller, 40- to

 

      60-percent increase with azithromycin.

 

                These changes are within the overall range

 

      of melagatran exposures in patients, and as

 

      outlined in detail in your briefing document,

 

      investigation into the potential impact of this

 

      pharmacokinetic interaction found no signal for

 

      increases bleeding events or increased ALT

 

      elevations in the approximately 230 patients

 

      receiving ximelagatran and macrolide antibiotics in

 

      the long-term studies.  These data do not suggest

 

      an important clinical impact of these

 

      pharmacokinetic interactions.

 

                We have conducted many other interaction

 

      studies where we've found no significant

 

                                                                29

 

      pharmacokinetic interactions.  As shown by the mean

 

      melagatran AUC ration and the 90-percent confidence

 

      interval within or slightly outside the 0.8 to 1.25

 

      no interaction interval.  The drugs investigated

 

      include alcohol, common cardiovascular medications,

 

      an NSAID, a sedative, and several antibiotics.

 

      These results are consistent with population

 

      pharmacokinetic analyses indicating a lack of

 

      interaction with commonly used comedications in the

 

      patient studies.  Taken together, these data

 

      suggest that ximelagatran has a low potential for

 

      drug interactions.

 

                Melagatran is primarily renally eliminated

 

      from plasma, and so we've carefully investigated

 

      the impact of renal function on the pharmacokinetics of

 

      ximelagatran.  In the three patient

 

      populations under consideration today, melagatran

 

      exposure increases as calculated creatinine

 

      clearance decreases.  For this reason, severe renal

 

      impairment, a calculated creatinine clearance less

 

      than 30 mLs per minute, was an exclusion criteria

 

      for our clinical studies, and we're currently

 

                                                                30

 

      investigating an alternative dosing strategy in

 

      that population.

 

                It's notable that we've gathered

 

      considerable experience with ximelagatran in

 

      patients with mild to moderate renal impairment as

 

      approximately 45 percent of the Phase III patient

 

      population had a calculated creatinine clearance

 

      between 30 and 80 mLs per minute.  The median

 

      exposures in these patients are about 1.5 to 2.5

 

      times higher, respectively, than patients with

 

      normal renal function, but there's considerable

 

      overlap in melagatran exposure between groups,

 

      suggesting dose adjustment was not necessary.

 

                We've also studied the potential effects

 

      on the pharmacokinetics of ximelagatran within

 

      other special populations, and other than

 

      differences in renal function between groups, we

 

      have not identified other important effects of age,

 

      gender, race, obesity--as measured using body mass

 

      index--or body weight on the pharmacokinetics of

 

      ximelagatran.

 

                The agency has suggested there should be a

 

                                                                31

 

      dose adjustment for ximelagatran in patients with

 

      renal impairment given the higher levels of

 

      melagatran in these patients.  But I'd like to show

 

      you why a fixed dose, as used in our clinical

 

      studies, is appropriate across the patient

 

      populations studied.

 

                We do agree with the agency's assessment

 

      that there's no need for dose adjustment in

 

      orthopedic surgery patients and that there was no

 

      increased bleeding related to melagatran exposure

 

      in VTE secondary prevention patients.  We do

 

      acknowledge an association between increasing

 

      melagatran exposure and increasing incidence of

 

      major bleeding in atrial fibrillation patients.

 

      But this relationship appears confounded by the

 

      correlation between melagatran exposure and the

 

      age-related decrease in calculated creatinine

 

      clearance.

 

                Shown here from the SPORTIF trials is the

 

      relationship between calculated creatinine

 

      clearance and major bleeding.  As you can see,

 

      major bleeding increased with declining renal

 

                                                                32

 

      function whether patients received ximelagatran or

 

      INR-controlled warfarin.  This suggests the

 

      increase in melagatran concentrations in patients

 

      with renal impairment is not associated with

 

      increased bleeding versus INR-controlled warfarin.

 

                It's also important to note that stroke

 

      risk increased with decreasing calculated

 

      creatinine clearance, and the vast majority of

 

      these strokes were ischemic.  So there's a

 

      possibility that a dose reduction in renally

 

      impaired patients intended to decrease bleeding may

 

      increase the risk of stroke in those patients at

 

      highest risk.

 

                We should also consider the hepatic

 

      findings, as will be presented by Dr. Sheth, and we

 

      have examined the possible relationship between

 

      melagatran exposure and ALT elevations.  As pointed

 

      out in our briefing document, we have observed an

 

      association between increasing melagatran exposure

 

      and increasing ALT elevations greater than 3 times

 

      upper limit of normal, but this relationship is

 

      very weak.  And as shown here, the relationship

 

                                                                33

 

      between melagatran AUC and peak ALT elevation in

 

      individual patients, while statistically

 

      significant, does not suggest a clear relationship

 

      between melagatran exposure and ALT elevations.

 

                In addition, we agree with the agency's

 

      conclusion that, aside from the ALT elevations

 

      noted with ximelagatran, there is no difference in

 

      the overall adverse event profile between

 

      ximelagatran and comparators in the long-term

 

      dosing study pool.

 

                Factoring in the occurrence of major

 

      bleeding, stroke and systemic embolic events, ALT

 

      elevations, and the overall adverse event profile,

 

      the observation of increased plasma melagatran

 

      concentrations in renal impairment does not appear

 

      to justify a dose reduction in these patients.  We

 

      believe our data support a fixed dose of

 

      ximelagatran in the patient populations studied.

 

                Now I'd like to show the steady-state

 

      plasma concentrations of melagatran in atrial

 

      fibrillation patients receiving a fixed dose of 36

 

      milligrams ximelagatran twice daily.  There are

 

                                                                34

 

      four key points here.

 

                Plasma concentrations fluctuate during the

 

      dosing interval, remaining largely above 0.05

 

      micromolar and infrequently exceeding 1 micromolar.

 

                Mean trough melagatran concentrations

 

      after 36 milligrams are approximately 0.2

 

      micromolar.  So should a patient miss a dose of

 

      ximelagatran, the 4- to 5-hour half-life of

 

      melagatran means that low but pharmacologically

 

      active concentrations remain for up to 24 hours

 

      post-dosing.  And the effect of melagatran is gone

 

      once it is cleared from plasma by the kidneys.

 

                This emphasizes the importance of

 

      maintaining good diuresis in the management of

 

      bleeding.  And while there is no specific antidote,

 

      if needed, melagatran can be dialyzed.

 

                And, lastly, the APTT is prolonged in

 

      patients and may help identify a residual

 

      anticoagulant effect.

 

                A critical aspect of oral anticoagulation

 

      is maintenance of a stable effect over time, and we

 

      have confirmed the long-term stability of oral

 

                                                                35

 

      ximelagatran.  Shown in yellow are the plasma

 

      concentrations of melagatran in atrial fibrillation

 

      patients in the Phase II study, SPORTIF II.  We

 

      remeasured plasma melagatran concentrations in a

 

      subset of those same patients between 13 to 16

 

      months later in SPORTIF IV, a long-term

 

      continuation study of SPORTIF II.

 

                The mean plasma concentrations of

 

      melagatran are completely overlapping, and the

 

      variability in exposure within individual patients

 

      was low, with a coefficient of variation of 25

 

      percent, indicating that oral ximelagatran results

 

      in stable and reproducible plasma concentrations of

 

      melagatran with long-term repeated dosing.  This

 

      stability enabled us to conduct our clinical

 

      studies using a fixed dose without coagulation

 

      monitoring.

 

                So we can conclude from this extensive

 

      clinical pharmacology program pharmacologically

 

      active concentrations of melagatran are rapidly

 

      achieved and maintained in a broad range of

 

      patients.  There is also no effect of food or

 

                                                                36

 

      alcohol and a low potential for drug interactions.

 

                The key attributes of ximelagatran are,

 

      therefore, its oral availability, rapid onset of

 

      action, low potential for drug interactions, and

 

      use at a fixed dose without coagulation monitoring.

 

                Now I'd like to introduce Dr. Jay Horrow,

 

      who will provide to you an evaluation of the

 

      efficacy of ximelagatran demonstrated in Phase III

 

      clinical studies.

 

                DR. BORER:  We'll just stop for one moment

 

      to make sure there are no issues that need to be

 

      clarified.  The relation of renal function to

 

      melagatran exposure undoubtedly is going to be

 

      discussed to a greater extent later, but I think we

 

      should hold that until we hear from the FDA

 

      presentations, and then we can talk about that.

 

      But if there are any issues that need to be

 

      clarified regarding the pharmacology, we should do

 

      that now.

 

                Steve?

 

                DR. NISSEN:  Two very brief questions.  Is

 

      anything known about the mechanism of macrolide

 

                                                                37

 

      interaction?  Have you explored that at all?

 

                DR. SARICH:  Yes.  We were slightly

 

      surprised to find that interaction since we don't

 

      interact with the P-450 system.  It appears that

 

      the interaction involves transport proteins of some

 

      kind, and we've looked at a range of different

 

      compounds that we've investigated, and it at this

 

      point appears isolated to the macrolide antibiotics

 

      we've studied.

 

                DR. NISSEN:  And the second question is:

 

      You showed the coagulation effect during therapy,

 

      and I wondered if you have additional data on what

 

      happens in, let's say, the first 72 to 96 hours

 

      after terminating therapy.  Is there evidence of a

 

      rebound phenomenon?

 

                DR. SARICH:  We have not observed that

 

      pharmacologically, as far as coagulation time

 

      assays.

 

                DR. NISSEN:  Okay.  But that has been

 

      studied.

 

                DR. SARICH:  We've followed out to 24

 

      hours after single-dose administration and not seen

 

                                                                38

 

      any evidence--

 

                DR. NISSEN:  But not longer than 24 hours?

 

                DR. SARICH:  Not that I can recall.

 

                DR. BORER:  John?

 

                DR. TEERLINK:  The other question I have

 

      is:  In terms of the relationship between the

 

      melagatran AUC versus the peak ALT elevations, how

 

      was the melagatran AUC derived?

 

                DR. SARICH:  Yes, these were derived using

 

      a population pharmacokinetic model.  So the

 

      patients that received ximelagatran in the Phase

 

      III clinical studies had plasma samples collected.

 

      Over 80 percent of the Phase III patient

 

      population--in the long-term population had a

 

      plasma sample collected.  Using a pharmacokinetic

 

      model that was developed by the team, we were able

 

      to estimate the exposure to melagatran in those

 

      patients.

 

                DR. BORER:  Ron Portman?

 

                DR. PORTMAN:  Noting differences in the

 

      chronopharmacology of drugs, were the curves you

 

      showed similar for both the morning and evening

 

                                                                39

 

      doses?

 

                DR. SARICH:  Are you speaking about the

 

      coagulation time assay--

 

                DR. PORTMAN:  No.  I was talking about the

 

      plasma concentrations.

 

                DR. SARICH:  Pharmacokinetics?

 

                DR. PORTMAN:  Right, pharmacokinetics.

 

                DR. SARICH:  Yes, they are consistent

 

      under administration during the day or overnight.

 

                DR. BORER:  Jonathan, go ahead.

 

                DR. SACKNER-BERNSTEIN:  In the analysis

 

      that you showed the stability of the concentrations

 

      of the drug over time from the SPORTIF II and

 

      SPORTIF IV population, did you perform that

 

      analysis restricting to patients who had samples at

 

      both times?  Because the analysis you showed had a

 

      larger population at baseline compared to a subset

 

      later.

 

                DR. SARICH:  Right.  We've done it both

 

      ways.  The figure actually represents the larger

 

      number in the SPORTIF II study and a smaller number

 

      in SPORTIF IV.  The intra-subject variability I

 

                                                                40

 

      noted was only the subjects that had sampling at

 

      both time occasions.

 

                DR. BORER:  Alan?

 

                DR. HIRSCH:  In the PK and AUC curves that

 

      you've generated, were there any changes or

 

      differences noted based on ethnicity, geographic

 

      sampling of a population, or gender?

 

                DR. SARICH:  Are you asking pharmacokinetic--

 

                DR. HIRSCH:  Yes, PPK differences between

 

      subgroups.

 

                DR. SARICH:  The main factor we've

 

      observed between any subgroups has been differences

 

      in renal function, calculated creatinine clearance.

 

      We have not observed any significant effects of

 

      other demographic parameters, age, gender, race,

 

      BMI, body weight.  It appears that exposure--the

 

      most influential demographic factor is calculated

 

      creatinine clearance.

 

                DR. BORER:  Susanna?

 

                DR. CUNNINGHAM:  Did you have a sufficient

 

      African American population to actually know

 

                                                                41

 

      anything about what the African American area of

 

      the curve might be or handling of the drug?

 

                DR. SARICH:  We have performed pharmacokinetic

 

      studies in that population.  I should say

 

      both--I'll show you some data here from a small

 

      study.  It's not African Americans per se, but it

 

      was a study in Europe, in Paris, in fact, where we

 

      had 12 blacks, 12 Asians, and 12 Caucasians, and

 

      found no real differences between these groups.

 

                If we looked at the entire patient

 

      population, we can see here--if we look at--you can

 

      see the Caucasian population here.  There's over

 

      6,000 patients.  The blacks where we had

 

      appropriate pharmacokinetic information, were 115,

 

      as well as Asians, and the category of other, and

 

      no differences between these populations.

 

                DR. BORER:  Tom?

 

                DR. PICKERING:  Do you have any data on

 

      interaction with aspirin?

 

                DR. SARICH:  Yes, we have performed

 

      actually two studies with aspirin.  There's no

 

      pharmacokinetic interaction with aspirin.  We see

 

                                                                42

 

      an additive effect on the capillary bleeding time,

 

      which is somewhat expected.

 

                DR. BORER:  Beverly?

 

                DR. LORELL:  Yes, with regard to body

 

      size, you commented on and emphasized obesity.

 

      What about the other end of the scale, very small

 

      body size?  Sometimes an issue in elderly women who

 

      might be candidates for several of these

 

      indications.

 

                DR. SARICH:  We have less data in very

 

      small individuals, but what we know about that

 

      population is that it's primarily their calculated

 

      creatinine clearance that influences their

 

      exposure.

 

                DR. BORER:  Jonathan?

 

                DR. SACKNER-BERNSTEIN:  I know we're going

 

      to get back to the renal function question, but

 

      there was one set of slides you showed where you

 

      tried to give us some reassurance about the

 

      relationship between bleeding and renal function.

 

      And you showed the risk of bleeding as calculated

 

      creatinine clearance reached the low end of the

 

                                                                43

 

      spectrum.

 

                I wonder if you performed any sort of

 

      retrospective power calculation on your ability to

 

      detect a difference in risk, in particular in the

 

      patients who we may be likely to see treated with

 

      this drug in clinical practice, those over 70, over

 

      75, where calculated creatinine clearances often

 

      are in the 40s.  So do you have an analysis there

 

      between 30 and 50 with conditional power to

 

      actually detect a difference in bleeding risk

 

      there.

 

                DR. SARICH:  I think we could probably

 

      best address that after the presentations.  We do

 

      have data there, and rather than getting into that

 

      discussion, if the Chair would agree, we could

 

      address that, bring an answer to you for that.

 

                DR. BORER:  Is that okay, Jonathan?

 

                DR. SACKNER-BERNSTEIN:  Yes.

 

                DR. BORER:  Okay.  Thank you.

 

      T1B                      DR. HORROW:  Ladies and

 

      gentlemen, I'm Dr. Jay Horrow from AstraZeneca.  We

 

      will now present Phase III data demonstrating that

 

                                                                44

 

      ximelagatran is an effective oral anticoagulant.

 

                In the first indication, long-term

 

      secondary prevention of venous thromboembolism, we

 

      will show ximelagatran superior to placebo.  In the

 

      second indication, prevention of VTE after total

 

      knee replacement, ximelagatran was superior to

 

      well-controlled anticoagulation with warfarin.  And

 

      in the chronic prevention of stroke, ximelagatran

 

      was noninferior to warfarin.

 

                These indications represent a broad range

 

      of patient populations.  We'll begin with the first

 

      one:  secondary prevention of VTE.

 

                Evidence has been accumulating that

 

      patients with acute VTE benefit from prolonged

 

      anticoagulation after acute treatment.  The THRIVE

 

      III trial comparing ximelagatran to placebo

 

      contributes to this growing body of evidence.

 

      Randomized patients had an acute symptomatic VTE

 

      objectively confirmed and had completed 6 months of

 

      treatment without VTE recurrence, also objectively

 

      documented at randomization.  Anticoagulation was

 

      desirable but not essential for these patients,

 

                                                                45

 

      that is, they had idiopathic VTE or probable

 

      hypercoagulable conditions.  Health status had to

 

      be compatible with survival for an additional 18

 

      months.

 

                In THRIVE III, 1,223 patients receives in

 

      double-blind fashion either oral ximelagatran 24

 

      milligrams twice daily or placebo for up to 18

 

      months.  Selection of 24 milligrams for this trial

 

      came from a consideration of preclinical data and

 

      data from Phase II trials in the orthopedic surgery

 

      indication.  These PK data from a Phase II European

 

      trial in patients undergoing hip or knee

 

      replacement demonstrate that administration of 8

 

      milligrams ximelagatran twice daily, the lowest

 

      curve, achieves plasma melagatran concentrations of

 

      about 0.05 micromolar.  This is the level at which

 

      anticoagulant activity with melagatran begins based

 

      on the data previously shown by Dr. Sarich.

 

                Progressively higher doses of oral

 

      ximelagatran, 12, 18, and 24 milligrams, achieved

 

      higher melagatran concentrations, more anticoagulant

 

      activity, and more time above the 0.05

 

                                                                46

 

      micromolar threshold for each dose.

 

                Outcome data from that same orthopedic

 

      surgery trial suggest that 24 milligrams is the

 

      most promising dose for efficacy.  The 24-milligram

 

      dose also had a reassuring bleeding profile.  We

 

      chose 24 milligrams for THRIVE III with placebo

 

      comparator without establishing dose-limiting

 

      toxicity, in this case bleeding.  The choice was an

 

      informed judgment taking into consideration, first,

 

      the need for efficacy demonstrated by the benefits

 

      seen here in joint replacement, an intense

 

      thrombotic stimulus; and, second, the need to avoid

 

      excess bleeding because the standard of care is no

 

      anticoagulant therapy at all.

 

                The trial compared ximelagatran to placebo

 

      in the rate of recurrence of symptomatic,

 

      objectively confirmed VTE.  VTE encompasses both

 

      deep vein thrombosis, DVT, and pulmonary embolism,

 

      PE, because PE originates from a thrombus in the

 

      systemic venous circulation, whether overt or not.

 

                The primary endpoint compared ximelagatran

 

      to placebo using a time-to-event analysis.  A

 

                                                                47

 

      recurrence of VTE required signs or symptoms of

 

      VTE, that is, a clinical event, and subsequent

 

      objective confirmation.  A blinded independent

 

      endpoint committee evaluated and adjudicated all

 

      clinical endpoints, including major bleeding

 

      events.

 

                The ximelagatran- and placebo-treated

 

      cohorts displayed similar demographic profiles.  As

 

      indicated by creatinine clearance between 30 and

 

      80, 23 percent had some degree of renal impairment.

 

      The index VTE event was or included pulmonary

 

      embolism for more than one-third of patients.  This

 

      Kaplan-Meier curve shows the cumulative incidence

 

      of the primary outcome in the ximelagatran and

 

      placebo groups, analyzed by intention to treat.

 

      Seventy-one patients in the placebo group suffered

 

      recurrent VTE, including 23 PEs, for a cumulative

 

      rate of 12.6 percent, while only 12 patients in the

 

      ximelagatran group had recurrent VTE, including

 

      only two PEs, for a cumulative rate of 2.8 percent.

 

      The 9.8-percent difference, significant at p less

 

      than 0.0001 by log rang test indicates that one VTE

 

                                                                48

 

      recurrence is prevented by ximelagatran treatment

 

      for up to 18 months to 10 patients.  The associated

 

      hazard ratio, 0.16, indicates a risk reduction of

 

      84 percent by ximelagatran relative to placebo.

 

                The composite endpoint of total VTE

 

      included both DVT and PE.  Benefit of ximelagatran

 

      over placebo occurred for each component of this

 

      composite endpoint--clinical DVT, clinical PE, and

 

      their combination.

 

                The superiority of ximelagatran to placebo

 

      is robust to multiple, prespecified sensitivity

 

      analyses listed here.  Each comparison demonstrated

 

      a significance level less than 0.0001

 

                Here we examine efficacy in subpopulations.  Small

 

      diamonds depict point estimates of

 

      the odds ratios of ximelagatran to placebo, and

 

      horizontal bars show their 95-percent confidence

 

      intervals.  Superiority of ximelagatran over

 

      placebo remains in all subgroups strata of

 

      reasonable size.

 

                In THRIVE III, the oral thrombin inhibitor

 

      ximelagatran, 24 milligrams twice daily for up to

 

                                                                49

 

      18 months, effectively reduced the number of

 

      recurrent VTE events following 6 months' treatment

 

      of an acute VTE.  The results are robust and

 

      consistent across multiple endpoints and subgroups

 

      and demonstrate a clinically relevant benefit.

 

                The second indication under review today

 

      is the prevention of VTE in patients undergoing

 

      knee replacement surgery.  Major joint replacement

 

      surgery challenges any anticoagulant to prevent VTE

 

      without counteracting surgical hemostasis.  VTE

 

      prevention contributes heavily to the benefit/risk

 

      balance for joint replacement surgery.

 

                The current options to reduce the

 

      occurrence of VTE after total knee replacement

 

      include the injectable agents low-molecular-weight

 

      heparin and fondaparinux and oral warfarin.  One

 

      FDA comment regards the choice of warfarin as the

 

      comparator for these trials.

 

                We chose warfarin for several reasons:

 

                First, it is the agent most commonly used

 

      for this purpose in North America, and we

 

      administered warfarin, as orthopedic surgeons do,

 

                                                                50

 

      beginning the night of surgery.

 

                Second, warfarin, like

 

      low-molecular-weight heparin, is a Grade 1A

 

      recommended therapy for this purpose, according to

 

      current American College of Chest Physicians

 

      Consensus Conference Guidelines.

 

                And, third, warfarin is associated with

 

      less bleeding than the injectable anticoagulants

 

      and so is a more daunting comparator for

 

      ximelagatran in terms of surgical hemostasis.

 

                Two independent double-blind Phase III

 

      trials--EXULT A and EXULT B--enrolled patients

 

      undergoing primary elective total knee replacement.

 

      EXULT A studied 24 and 36 milligrams ximelagatran

 

      and warfarin.  We had studied 24 milligrams in this

 

      context previously and found protection similar to

 

      but not better than warfarin at p equal 0.07.  We

 

      found that result surprising.  Unsure whether or

 

      not it was a Type II error, we designed EXULT A

 

      with two ximelagatran arms:  one using 24

 

      milligrams and the other using 36 milligrams.

 

                Warfarin and its paired placebo began, as

 

                                                                51

 

      typically practiced in the U.S., the evening of the

 

      day of surgery while ximelagatran and its placebo

 

      began early on the morning after the day of

 

      surgery.  Treatment continued for 7 to 12 days,

 

      after which all patients underwent bilateral

 

      venography.

 

                Based on the results of EXULT A, EXULT B

 

      studied only 36 milligrams ximelagatran and

 

      warfarin.  Warfarin was aggressively and

 

      successfully dosed to drive the INR rapidly to its

 

      target of 2.5, with an accepted range of 1.8 to

 

      3.0.  The primary outcome formed the composite of

 

      distal and proximal DVT by venogram performed

 

      between days 7 and 12, objectively confirmed

 

      symptomatic DVT or pulmonary embolism up to 2 days

 

      after venography, and all-cause mortality up to 2

 

      days after venography.  Both trials utilized the

 

      same blinded independent committee for event

 

      adjudication.

 

                The treatment groups in the EXULT trials

 

      were balanced and represented well the population

 

      of patients in the United States undergoing total

 

                                                                52

 

      knee replacement.  More than a third of the cohort

 

      displayed some degree of renal impairment.

 

                Here are the primary results for EXULT A

 

      and EXULT B.  In EXULT A, ximelagatran 36

 

      milligrams, in yellow, showed superiority to

 

      well-controlled anticoagulation with warfarin, in

 

      gray, at p equals 0.003.  EXULT B confirmed those

 

      results, with p less than 10                                              

                               -5.  These results yield

 

      relative risk reductions of 26 and 29 percent and

 

      numbers needed to treat of 14 and 11, respectively.

 

                In EXULT A, ximelagatran 24 milligrams, in

 

      orange, and warfarin, in gray, did not differ, with

 

      event rates of 24.9 and 27.6 percent, respectively.

 

      That p value is 0.28.

 

                The delay in anticoagulation with warfarin

 

      administration suggests that it may act like a

 

      placebo in EXULT.  In fact, warfarin rates, in

 

      gray, are the lowest ever obtained in knee

 

      replacement clinical trials with warfarin, perhaps

 

      because of the rapid achievement in EXULT of

 

      therapeutic INRs.  Placebo rates are historically

 

      over 60 percent, and the mean INR in EXULT was 2.4

 

                                                                53

 

      on post-op day 3.  The warfarin group provided a

 

      formidable comparator for ximelagatran in the EXULT

 

      studies.

 

                Here we see results for the components of

 

      the composite primary endpoint.  As expected, the

 

      majority of events occurred in the distal leg.

 

      Rates for proximal DVT, for PE, and for death were

 

      low in all treatment groups.  Another point raised

 

      by FDA is how clinically relevant distal DVT is as

 

      a component of that endpoint.  It's important to

 

      note that 10 to 20 percent of distal thrombi extend

 

      to become proximal thrombi, and either one can

 

      cause pulmonary embolism, making all three

 

      phenomena clinically relevant components of a

 

      composite endpoint.  In fact, proximal and distal

 

      deep vein thrombosis detected by venography,

 

      whether symptomatic or not, is a primary endpoint

 

      historically accepted by the agency for VTE

 

      prophylaxis registration trials.

 

                This display of the primary outcome by

 

      subgroup strata shows differences in event

 

      incidences between the pooled 36-milligram

 

                                                                54

 

      ximelagatran and pooled warfarin groups.  These

 

      results, with small numbers in just a few

 

      subgroups, reveal no discrepancies in efficacy in

 

      any particular subpopulation.

 

                Oral ximelagatran, 36 milligrams, provided

 

      superior protection against VTE and all-cause

 

      mortality compared with well-controlled

 

      anticoagulation with adjusted-dose warfarin, a

 

      clinically relevant comparator.  This superior

 

      protection was consistent across multiple

 

      subgroups.  These data support the efficacy of

 

      ximelagatran for the indication requested.

 

                The third indication considered today is

 

      the protection of patients from stroke and other

 

      thromboembolic complications of atrial

 

      fibrillation.  We have demonstrated that

 

      ximelagatran provides this protection, as well as

 

      does warfarin, across a broadly based patient

 

      population.

 

                Two independent pivotal trials--SPORTIF

 

      III, dosed, open-label in 23 countries in Europe

 

      and Asia, and SPORTIF V, conducted double-blind in

 

                                                                55

 

      North America--enrolled patients eligible for

 

      warfarin therapy according to existing treatment

 

      guidelines, that is, those with nonvalvular atrial

 

      fibrillation with at least one additional risk

 

      factor for stroke.  Each SPORTIF trial by itself

 

      studied more patients than all previous trials of

 

      stroke prevention in atrial fibrillation combined.

 

      Each trial compared 36 milligrams twice daily

 

      ximelagatran to dose-adjusted warfarin in

 

      preventing all strokes and systemic embolism, hard

 

      clinical endpoints in an intention-to-treat

 

      fashion.

 

                The choice of 36 milligrams came from

 

      several considerations.  There is no surrogate

 

      marker for stroke and systemic embolism, and both

 

      events are devastating.  Thus, we performed a

 

      dose-ranging study for safety and tolerability of

 

      ximelagatran 20, 40, and 60 milligrams in SPORTIF

 

      II, a 3-month Phase II atrial fibrillation study.

 

      While the numbers were small in that study,

 

      bleeding was most frequent with 60 milligrams and

 

      also the warfarin comparator, and less frequent

 

                                                                56

 

      with 20 or 40 milligrams ximelagatran.  We knew

 

      that 24 milligrams was effective in the Phase II

 

      European orthopedic surgery program and reasoned

 

      that any downside impact of potential additional

 

      strokes with 24 milligrams would be far worse than

 

      the bleeding seen with 36 milligrams in this

 

      nonsurgical context.  Using this educated judgment,

 

      we chose 36 milligrams in the Phase III atrial

 

      fibrillation program.

 

                Let's take a moment to consider the

 

      open-label nature of the SPORTIF III trial.  The

 

      majority of prior stroke prevention trials in

 

      atrial fibrillation also utilized an open-label

 

      format based on the difficulty of managing

 

      anticoagulation in blinded fashion.  SPORTIF III

 

      featured open-label dosing at sites, but also

 

      centrally randomized allocation and two additional

 

      levels of blinding:  blinded local assessment of

 

      primary endpoints by study-affiliated neurologists,

 

      and blinded independent central committee

 

      adjudication of all study endpoints.  SPORTIF V

 

      featured double-blind, double-dummy medication, and

 

                                                                57

 

      for patients receiving ximelagatran and placebo

 

      warfarin, sham INR values that mimicked those

 

      obtained during warfarin therapy.

 

                The established efficacy of warfarin

 

      precluded a placebo comparison.  Because warfarin

 

      is so efficacious, it is reasonable to establish

 

      ximelagatran efficacy in comparison to warfarin,

 

      and we did so using a noninferiority design.  In

 

      consultation with an executive steering committee

 

      and data safety monitoring board compose of leaders

 

      of prior stroke prevention trials and a

 

      statistician expert in noninferiority trials, we

 

      prespecified a 2-percent per year absolute

 

      noninferiority margin.  The choice of this margin

 

      has been questioned.  The choice of 2 percent arose

 

      partly from an expected 3.1 percent warfarin rate,

 

      but more importantly, from consideration of the

 

      clinically tolerable absolute difference in stroke

 

      rates considering warfarin's overall clinical

 

      profile.  A similar consideration drove designers

 

      of the SPAF III trial to power that trial to detect

 

      a 2-percent per year event rate with upper

 

                                                                58

 

      confidence bounds of 3 for a population at lower

 

      risk of stroke.  Even so, we prespecified a more

 

      conservative 2-percent upper confidence limit.  The

 

      point estimate of the difference in event rates

 

      needs to be much smaller than 2 percent for the

 

      worst case, that is, the upper confidence limit, to

 

      be less than 2.

 

                The strength of the 2-percent per year

 

      absolute margin resides in its clinical relevance,

 

      its prespecification, and that it is conservative.

 

                At screening, those patients already

 

      taking oral anticoagulants interrupted that therapy

 

      to decrease INR to 2 or less by the time of

 

      randomization, at which time patients received

 

      either warfarin or ximelagatran.  Each trial

 

      achieved a degree of warfarin control rarely found

 

      in routine clinical practice.  The warfarin-treated

 

      groups constituted formidable comparators for

 

      ximelagatran, particularly in SPORTIF V.  Samsa and

 

      colleagues found that most patients taking warfarin

 

      spend more than half the time on treatment outside

 

      the therapeutic range.  In SPORTIF V, only 15

 

                                                                59

 

      percent of patients did so.

 

                The ximelagatran- and warfarin-treated

 

      cohorts displayed nearly identical demographic

 

      profiles in each independent Phase III trial, seen

 

      here as pooled data.  Patients reflected well the

 

      elderly population of nonvalvular atrial

 

      fibrillation patients requiring anticoagulation for

 

      stroke prophylaxis, and the majority had impaired

 

      renal function.

 

                In SPORTIF III, warfarin, shown in gray,

 

      displayed an event rate of 2.3 percent per year

 

      compared to 1.6 percent per year with ximelagatran,

 

      shown in yellow.

 

                In SPORTIF V, the rates were 1.2 for

 

      warfarin, in gray, and 1.6 for ximelagatran, in

 

      yellow.

 

                Primary event rates with ximelagatran are

 

      nearly identical in SPORTIF III and SPORTIF V.  For

 

      warfarin, the rates fall within the range of event

 

      rates in previous trials, 0.6 to 4.1 percent per

 

      year.

 

                For comparison, the pooled rate in prior

 

                                                                60

 

      stroke trials for patients in this risk category

 

      taking placebo or aspirin was over 8 percent per

 

      year.  The difference in event rates in SPORTIF

 

      III, 0.66, favoring ximelagatran, had an upper

 

      confidence limit of 0.13, less than the

 

      prespecified 2-percent margin.  In SPORTIF V, the

 

      difference of 0.5 favoring warfarin had an upper

 

      bound of 1.03, also less than the prespecified

 

      2-percent per year margin.  Thus, each trial

 

      independently succeeded by satisfying the

 

      prespecified noninferiority criterion for the

 

      primary outcome.

 

                As expected, most of the events in this

 

      composite outcome were ischemic strokes.

 

      Hemorrhagic stroke and systemic embolism occurred

 

      more rarely and did not influence the primary

 

      endpoint substantially.

 

                Several sensitivity analyses confirmed the

 

      results of the primary analysis.  One such

 

      analysis, depicted here, included all-cause

 

      mortality in the primary endpoint at the suggestion

 

      of the agency.  SPORTIF III returned event rates of

 

                                                                61

 

      4.2 and 5.1 for a difference of 0.87 favoring

 

      ximelagatran, while SPORTIF V rates were nearly

 

      identical at 4.7 and 4.8.

 

                Adding all-cause mortality shifted each

 

      study's event rate difference point estimate to the

 

      left in favor of ximelagatran.

 

                Another sensitivity analysis, depicted

 

      here, used an on-treatment approach using the same

 

      endpoints and the same population, but not counting

 

      events that occurred after stopping study treatment

 

      for 30 continuous or 60 total days.  The upper

 

      bound of negative 0.18 indicates superiority in

 

      SPORTIF III.  The value of 1.2 in SPORTIF V

 

      indicates noninferiority to well-controlled

 

      warfarin.

 

                For each trial, we also performed a paper

 

      comparison of ximelagatran to placebo by factoring

 

      in the results of the six prior stroke prevention

 

      trials.  We obtained original data from those

 

      trials to utilize the same endpoint events as in

 

      SPORTIF.  Demographics of patients in these trials

 

      were similar to those of SPORTIF patients.

 

                                                                62

 

                In these calculations, SPORTIF III and

 

      SPORTIF V separately demonstrated statistically

 

      significant risk reductions for ximelagatran

 

      relative to putative placebo, as did the pooled

 

      SPORTIF data.  Ximelagatran works as an

 

      anticoagulant in this population.

 

                As before, here we see differences in

 

      primary event rates according to demographic

 

      subgroups.  These pooled results reveal no

 

      discrepancies in any particular subpopulation,

 

      including the elderly, women, the obese, and those

 

      with poor renal function.

 

                In conclusion, for atrial fibrillation

 

      each of two trials independently met its objective,

 

      demonstrating that 36 milligrams of ximelagatran

 

      taken twice daily prevented stroke and systemic

 

      embolism to an extent similar to that of

 

      well-controlled anticoagulation with warfarin.

 

                For long-term secondary VTE prevention,

 

      the THRIVE III trial demonstrated that 24

 

      milligrams ximelagatran twice daily prevented VTE

 

      recurrence compared to placebo.

 

                                                                63

 

                And in total knee replacement surgery, the

 

      two independent EXULT trials showed that 36

 

      milligrams twice daily prevented VTE and all-cause

 

      mortality better than dose-adjusted warfarin.

 

                Based on five pivotal trial, each the

 

      largest in its field, involving more than 12,000

 

      patients, these data establish the effectiveness of

 

      ximelagatran as an oral anticoagulant in a variety

 

      of patient populations at high risk for

 

      thromboembolism.

 

                Dr. Sunita Sheth will next address

 

      particular safety aspects of administration of

 

      ximelagatran for these indications.

 

                DR. BORER:  Thank you very much, Jay.

 

                Again, we'll take a minute to see if

 

      anyone has any issues that require clarification.

 

      Clearly, we are going to talk about or probably

 

      we're going to be talking about the selection of

 

      the delta for the noninferiority trial, but I don't

 

      want to get into that discussion now.  We have some

 

      extraordinary statistical fire power here between

 

      Tom on the committee and Lloyd Fisher and Jerry

 

                                                                64

 

      Faich sitting over there and the FDA statisticians.

 

      I think we'll wait on that until after all the

 

      presentations, including the FDA presentations,

 

      have been made.  But if we have any issues of fact

 

      that need to be clarified now, let's do it.

 

                Jonathan?

 

                DR. SACKNER-BERNSTEIN:  In the FDA

 

      briefing document, it points out that there were

 

      patients who were withdrawn from the study for whom

 

      there is not information about whether they

 

      underwent or suffered any events.  If that's

 

      correct, please clarify, because it looks as though

 

      from the study flow that that means in SPORTIF V as

 

      many as 15 percent of the patients we basically

 

      would not have any clinical outcomes data available

 

      from the point in time when they withdrew.  Is that

 

      correct?

 

                DR. HORROW:  We followed up on all of our

 

      patients in the SPORTIF III and V trials to the

 

      greatest extent possible, and, in fact, after we

 

      were done with our follow-up, at the time of final

 

      closure, locking the database, we were left, out of

 

                                                                65

 

      7,922 patients, with only 63 patients about whom we

 

      were unsure of their final status.

 

                DR. SACKNER-BERNSTEIN:  So that would mean

 

      that the FDA briefing document is incorrect,

 

      because the FDA briefing document states that--and

 

      I'm looking at page 36 of the clinical review from

 

      Cardio/Renal Division.  It says in the first

 

      paragraph that patients that were discontinued from

 

      study medication and withdrew from study were not

 

      followed for primary efficacy endpoints or death.

 

      And then as you turn to page 45 with the patient

 

      disposition in SPORTIF V, it looks as though

 

      there's 300 study withdrawals from the ximelagatran

 

      group and 286 from the warfarin group.  So that

 

      means that about 15 percent would have incomplete

 

      clinical outcomes data, but you're saying there's

 

      only 63.

 

                So could you explain for us where the

 

      disparity should be settled?

 

                DR. HORROW:  It is conceivable that there

 

      is a misinterpretation of the term "study drug

 

      discontinuation" and "withdrawal from study."  More

 

                                                                66

 

      likely, the misunderstanding may accrue from the

 

      follow-up efforts that we made to ascertain the

 

      vital status of every patient in the SPORTIF

 

      trials.

 

                We followed up on every patient, aside

 

      from the 63 that I just mentioned, and are

 

      confident in their vital status, knowing whether

 

      they were alive or dead, whether they had a stroke

 

      or not, in our database.

 

                DR. FLEMING:  Could I just clarify?  So I

 

      assume what you then did is you defined a date of

 

      data lock or closure where on that calendar date

 

      you wanted to follow all patients relative to their

 

      survival status and stroke status.  Are you saying

 

      then for all but 63 patients you knew their

 

      survival status and stroke status as of that

 

      calendar date for data lock?

 

                DR. HORROW:  Exactly, and that would be

 

      the data lock date for each respective

 

      trial--SPORTIF III and SPORTIF V.  That is correct.

 

                DR. BORER:  Steve?

 

                DR. NISSEN:  I want to make sure I

 

                                                                67

 

      understand how you maintained the blind,

 

      particularly in SPORTIF III.  Obviously with

 

      warfarin, you may require frequent dose adjustments

 

      and so on.  So in the open-label, particularly

 

      SPORTIF III, how did you maintain--in both trials,

 

      I'd like to understand the procedures that were

 

      undertaken.  I guess in the open-label trial there

 

      was no blinding, right?  The physicians and

 

      patients knew what they were receiving; is that

 

      correct?

 

                DR. HORROW:  In the open-label trial?

 

                DR. NISSEN:  Yes.

 

                DR. HORROW:  It was open-label dosing, and

 

      so you are correct that the physicians and the

 

      patients knew the drug, and the evaluators, the

 

      neurologists locally, and the central adjudication

 

      committee were blinded and didn't know.

 

                DR. NISSEN:  Okay, I understand.  And

 

      SPORTIF V, then, how did you adjust warfarin and

 

      maintain the blind?  Explain to me how that was

 

      done.

 

                DR. HORROW:  It was quite tricky and

 

                                                                68

 

      involved quite a bit of work on the basis of the

 

      investigators and quite a burden for the patients.

 

      In SPORTIF V, all of the INR values were obtained

 

      in almost all cases by only two

 

      laboratories--that's an incredible degree of

 

      standardization for thromboplastin--either the

 

      centralized laboratory or a point-of-care machine

 

      that had standardized cards.

 

                In each case--well, for the point-of-care

 

      machine, a coded number was produced by the

 

      machine.  That was called in to a central

 

      randomization area, and that service then faxed to

 

      the site either the true INR value if the patient

 

      was really in the warfarin group or a shammed INR

 

      value if the patient was truly taking ximelagatran.

 

      So the site was unaware when it received the fax

 

      what group the patient was in.

 

                If the test was done at the centralized

 

      laboratory, then the centralized laboratory

 

      likewise sent the results to the IBRS site, the

 

      specialized service, which then, again, faxed

 

      either the shammed or the true INR value to the

 

                                                                69

 

      site.

 

                DR. NISSEN:  And then dose adjustments,

 

      how were those then made?  I mean, obviously some

 

      of the patients needed a dose adjustment, so what

 

      happened then?

 

                DR. HORROW:  Well, as you know, for

 

      ximelagatran or its placebo there were no dose

 

      adjustments.  But for warfarin or its placebo, each

 

      investigator adjusted the dose based on their usual

 

      practice considering the patient and the INR value

 

      or shammed value--they didn't know which it

 

      was--they'd received by fax.

 

                DR. NISSEN:  So there was no--it was all

 

      done per local physician practice.  There was no

 

      standard applied to how dose adjustments were made.

 

      Is that right?

 

                DR. HORROW:  That's correct.  We did not

 

      require all the investigators to adjust their

 

      patients' warfarin doses against some standard.

 

      This was to be a very real-world--as much as we

 

      could--type of adjustment in terms of warfarin or

 

      shammed dosing.

 

                                                                70

 

                DR. NISSEN:  And I assume the reason you

 

      didn't do that in SPORTIF III was that you just

 

      felt it was too difficult.

 

                DR. HORROW:  In SPORTIF III, the

 

      investigators were very uncomfortable with blinded

 

      anticoagulation testing and were unwilling to move

 

      forward in that regard.

 

                In SPORTIF V, our North American

 

      investigators embraced the randomization somewhat

 

      more willingly.

 

                DR. NISSEN:  So you tried to do SPORTIF

 

      III blinded but they wouldn't go along with it?  I

 

      don't understand exactly what happened.

 

                DR. HORROW:  It was not possible to get

 

      the investigators in SPORTIF III to move forward

 

      with the blinded testing and anticoagulation.

 

                DR. NISSEN:  You attempted it, and then

 

      they weren't able to comply.  Is that what

 

      happened?

 

                DR. HORROW:  At an investigators meeting,

 

      there was--

 

                DR. NISSEN:  A rebellion.

 

                                                                71

 

                DR. HORROW:  There was no support.

 

                DR. BORER:  Okay.  Bill?  And then we have

 

      Tom and Alan and John.

 

                DR. HIATT:  A comment and a question.  In

 

      the knee replacement studies, you commented that

 

      you achieved a rapid increase in INR and that it

 

      was 2.4 at day 3.  And I just want to comment that,

 

      you know, there's an association between

 

      antithrombotic and anticoagulant effects of

 

      warfarin.  It takes 4 to 6 days for Factor II to be

 

      depleted, so that's a false sense of security

 

      around the measurement of the INR.  They're still

 

      not antithrombotic.

 

                So my question is:  If you take the

 

      three-quarters of patients at the end of that study

 

      who were, quote, therapeutic versus the one-quarter

 

      that were not, did you look at a subgroup analysis

 

      around difference in VTE rates at the end of that

 

      time?  Were the patients who were, in fact,

 

      therapeutic by that number equivalent in terms of

 

      VTE rates compared with the patients who were

 

      sub-therapeutic?

 

                                                                72

 

                DR. HORROW:  My understanding of the

 

      question is did we perform a subgroup analysis near

 

      the end of the treatment interval regarding

 

      patients--or based on the actual INRs of the

 

      patients.  We do not have that analysis.

 

                DR. HIATT:  I think the speculation would

 

      be that the differences would be erased in those

 

      who were therapeutic, and a major difference

 

      between treatments would have been in those who

 

      were sub-therapeutic.  That was my question.

 

                DR. HORROW:  This is quite possible, and

 

      it's important to understand that the EXULT trials

 

      mimicked warfarin administration in the orthopedic

 

      surgery realm as it is currently practiced today in

 

      the United States.  And so it was a very relevant

 

      way to look at the effects.

 

                DR. BORER:  Tom?

 

                DR. PICKERING:  Can you tell us how the

 

      INR control rates in the SPORTIF trials compared

 

      with the same rates in the six

 

      warfarin-versus-placebo trials?

 

                DR. HORROW:  The INR rates in the six

 

                                                                73

 

      index trials had somewhat of a spread, as would be

 

      expected, and it's actually possible to see that as

 

      the INR rates are better in some of those trials,

 

      so are the results in terms of the decrease in the

 

      warfarin event rate.  And our results for INR

 

      control were really quite in the middle, 2.5,

 

      2.4--could we have the previous slide, please?  I

 

      can show you some data on them.

 

                This would be for SPORTIF V, summary

 

      statistics.  Please note in the middle column

 

      labeled ximelagatran, we are looking at shammed

 

      values, and you will note that we have 2.5 at 3

 

      months for ximelagatran and 2.4 for warfarin, at 12

 

      months similarly, at 24 months similarly--right in

 

      the middle of the desired interval.  And, of

 

      course, the other thing that you might note here is

 

      that there is a threshold of 4.0 for the shammed

 

      values to ensure that no shammed value ended up

 

      putting a patient unnecessarily in the hospital

 

      because of an elevated shammed INR.

 

                Nevertheless, as you can see by the ranges

 

      here, it's quite clear that the investigators would

 

                                                                74

 

      be unable to determine whether a patient were in

 

      one group or the other.

 

                DR. PICKERING:  That really wasn't my

 

      question.  I was asking if there are comparable

 

      data for the six warfarin placebo trials.

 

                DR. HORROW:  I don't have those data

 

      available to show you at this time.

 

                DR. BORER:  I think they're in one of our

 

      two books, Tom.

 

                DR. HORROW:  I believe they may be in the

 

      briefing document.

 

                DR. BORER:  If I remember correctly, they

 

      do show a fairly wide range, as you might expect,

 

      but we can get those data.

 

                Okay.  Alan?

 

                DR. HIRSCH:  I have two questions.  One is

 

      to follow up Steve's question regarding the SPORTIF

 

      III blinding.  I just always believe it's terribly

 

      important to have blinding as a component of major

 

      pivotal trials, acknowledging that lack of blind

 

      can really alter outcomes in unexpected ways.  So I

 

      want to just run this through one more time.

 

                                                                75

 

                Pitying the investigators that would not

 

      go along with your request, the patients knew their

 

      study assignment, correct?

 

                DR. HORROW:  In SPORTIF III.

 

                DR. HIRSCH:  In SPORTIF III.

 

                DR. HORROW:  That's correct.

 

                DR. HIRSCH:  The physicians--

 

                DR. HORROW:  The patients knew their

 

      assignment, as did the principal investigators.

 

                DR. HIRSCH:  And coordinators.

 

                DR. HORROW:  That's correct.

 

                DR. HIRSCH:  So how would we have any

 

      confidence that the adjudicating neurologist would

 

      have any blind maintained at all?

 

                DR. HORROW:  Well--

 

                DR. HIRSCH:  I worry.

 

                DR. HORROW:  Your point is well taken that

 

      that cannot be assured with certainty.  We can say

 

      that there were efforts made to make sure that the

 

      neurologist was not told on purpose the assignment

 

      of the patient, and we know also that all members

 

      of the central adjudication committee, which

 

                                                                76

 

      evaluated all the endpoint events upon which the

 

      results are based, did so in a totally blinded

 

      fashion.

 

                DR. HIRSCH:  I guess if there was

 

      concordance between those two groups, I'm somewhat

 

      satisfied.

 

                Let me come back with a follow-up question

 

      for EXULT, if I could.  The data that we have

 

      demonstrates benefits of ximelagatran versus

 

      Coumadin preventing DVT in this population at risk

 

      after total knee replacement.  And as we'll discuss

 

      later, most of that data is regarding distal DVT,

 

      which I do care about.  But in the database, do we

 

      have any evidence, quality-of-life measurements,

 

      girths, anything that demonstrates a clinically

 

      relevant effect for the patient?  In other words,

 

      in the absence of venographic surveillance, would

 

      the patient know there was a difference in outcome?

 

                DR. HORROW:  I'd like to ask Dr. Scott

 

      Berkowitz, who is the medical director for that

 

      particular trial, to address that issue.  Dr.

 

      Berkowitz?

 

                                                                77

 

                DR. BERKOWITZ:  Hi.  Scott Berkowitz,

 

      AstraZeneca.  There was not any type of

 

      quality-of-life assessment in this short-term

 

      trial.  The symptomatic events were collected as

 

      well, including distal, proximal, and PEs.  They

 

      were low, as they are in TKR trials and did not see

 

      a difference, a statistical difference.

 

                DR. BORER:  There was a question I was

 

      going to hold until the end, but it seems to be

 

      relevant right here in view of Alan's point.  You

 

      probably have a back-up slide, and Alan just

 

      suggested that he probably has the data off the top

 

      of his head.  But can you tell us, among people

 

      historically from older trials where data would be

 

      available who have asymptomatic distal DVT and who

 

      aren't treated, what's the risk of subsequent

 

      thromboembolic events during some follow-up period?

 

                DR. BERKOWITZ:  Well, we don't have the

 

      greatest data on that, unfortunately, in the

 

      literature.  What we know is that 10 to 20 percent,

 

      depending on what you're readings--there are only

 

      three or four studies--do propagate from distal to

 

                                                                78

 

      proximal.  We know about 5 percent propagate to PE.

 

      We don't know the actual recurrence rate of what

 

      further DVTs would be after, say, 6 months.  We do

 

      also know that post-thrombotic syndrome occurs in 5

 

      percent of patients in 2 to 7 years after total

 

      knee replacement.  Those are the real data that we

 

      have.  Not an area well studied.

 

                DR. BORER:  Jonathan, and then Steve.

 

                DR. SACKNER-BERNSTEIN:  I noticed that in

 

      the trials for the study flow of patients in

 

      several of your trials, including THRIVE, both

 

      EXULTs, and SPORTIF V, that there is a number of

 

      patients listed as being enrolled and then a second

 

      number of patients listed as being randomized.  And

 

      there's very little information in either the FDA

 

      or the sponsor's documents about what happened to

 

      those patients.  So I'm wondering if you could

 

      describe it because in each of the cases you're

 

      looking at probably in the range of 10 percent of

 

      the patients who are enrolled that don't make it to

 

      randomization.

 

                DR. BERKOWITZ:  Maybe I'll first try to

 

                                                                79

 

      answer for the EXULT and THRIVE, and then ask Dr.

 

      Horrow for atrial fibrillation.

 

                For the EXULT trials, patients were

 

      enrolled, meaning that they were seen as an

 

      outpatient up to a month before the procedure, and

 

      then would come into the hospital, and if they had

 

      the surgery of interest, which was primary total

 

      knee replacement, then would be randomized,

 

      assuming they went through the eligibility

 

      criteria.  The most common reason patients wouldn't

 

      go from enrollment to randomization is that either

 

      the--there were two:  one, that the surgery was

 

      cancelled, and then the patient wasn't rescheduled

 

      for the procedure--excuse me, for the study, but

 

      did do the procedure; the other was that with these

 

      trials rapidly enrolling, we had many people lined

 

      up but then the study--we reached our enrollment.

 

      Those were the two major causes.

 

                For the THRIVE study, these were patients

 

      who had acute events for 6 months treated acute DVT

 

      and then went on to a 6-month--either placebo or to

 

      ximelagatran 24-milligram arm, and most of these in

 

                                                                80

 

      terms of just taking a look here--I can just show

 

      you what we've got in terms of that.  In terms of

 

      the ones that were not randomized, there were 123

 

      of those patients, and most of this turned out to

 

      be eligibility not fulfilled or withdrawn consent.

 

      And that is a common thing that patients might

 

      think more about the study if they want to

 

      participate in such a long-term--and then I could

 

      turn it over to Dr. Horrow.

 

                DR. HORROW:  In the SPORTIF trials, the

 

      major reason why patients were enrolled but not

 

      randomized was because of the failure of an

 

      eligibility criterion; in particular, the major one

 

      was the ability to achieve two electrocardiograms

 

      demonstrating atrial fibrillation in the manner

 

      specified.  And as a result, the principal

 

      investigators did not enroll a number of the

 

      patients whom they at first thought were good

 

      candidates.

 

                DR. SACKNER-BERNSTEIN:  Can I just follow

 

      up?  One quick point in follow-up.  In the patients

 

      enrolled in SPORTIF where many of them were coming

 

                                                                81

 

      off the vitamin K antagonist, how many--even if it

 

      was a minority, how many of those patients had some

 

      sort of clinical event that led them not to be

 

      randomized?

 

                DR. HORROW:  I understand your interest is

 

      in seeing what happens to the patients who came off

 

      of vitamin K antagonist in the enrollment period,

 

      did they happen to have events.  I believe that we

 

      have some data on that, although I can't say for

 

      sure that all of these did not enroll.  They may

 

      have had an event after enrollment.  If you'll just

 

      give me a moment, I'll see if we can find these

 

      data.

 

                Yes, thank you.  Here we see the number of

 

      patients with primary events who had an event

 

      within 30 days of discontinuing study drug, and

 

      this would be either the ximelagatran or the

 

      warfarin group.  And this would be during the

 

      course of the trial.  As you can see, there's not

 

      much difference between the two groups.

 

                I think this may address the question that

 

      you're getting at, which is what happens when

 

                                                                82

 

      patients discontinue their anticoagulant.

 

                DR. SACKNER-BERNSTEIN:  Well, actually, I

 

      find that reassuring, that information, but really

 

      what I was getting at was the impact of the

 

      strategy that would be proposed based on the study,

 

      which is you have a patient who's on long-term

 

      warfarin and you're going to convert them

 

      potentially to a new agent.  There's a period that

 

      would be followed where there's a transition, and

 

      I'd like to know if that transition period is a

 

      period that could be associated with risk as well.

 

                DR. HORROW:  I understand better.  Thank

 

      you.  Here are some data from SPORTIF III looking

 

      at primary events within 7 days of randomization.

 

      There were three patients who had a primary event

 

      in the SPORTIF III trial within 7 days of

 

      randomization, and, of course, the patients taking

 

      VKA--all patients had to stop their VKA in order to

 

      begin randomization.  And there were two events in

 

      the warfarin group and one in the ximelagatran

 

      group.

 

                DR. BORER:  Steve?

 

                                                                83

 

                DR. NISSEN:  I want to come back to the

 

      blinding issue again, and we've been dancing around

 

      it so let me just come to the point.

 

                Something extraordinary happened in

 

      SPORTIF III and SPORTIF V.  In SPORTIF III, I

 

      calculate a hazard ratio of 1.39, 1.40 that's in

 

      favor of ximelagatran.  And in SPORTIF V, the

 

      hazard ratio is 1.35 in favor of warfarin.  And so

 

      you have almost a completely opposite effect on the

 

      point estimates, which, you know, is really unusual

 

      when you consider the similarity of the trials.

 

                So we're al trying--we're all sitting here

 

      looking at the briefing document, and we're trying

 

      to figure out what could possibly have happened

 

      here so that, you know--I mean, there's essentially

 

      a 39-percent greater risk for warfarin in SPORTIF

 

      III and a 39-percent greater risk for ximelagatran

 

      in SPORTIF V.  And the only big difference in the

 

      two trials is that one was blinded and one wasn't.

 

                And so most rational people who look at

 

      that would say, well, we're going to believe the

 

      blinded results, we're not going to believe the

 

                                                                84

 

      unblinded results.  And so this is a real

 

      credibility issue, and I think we might as well

 

      just put it on the table and get your reaction to

 

      it.

 

                DR. HORROW:  In fact, there are many

 

      differences between SPORTIF III and SPORTIF V that

 

      are confounded with the open-label and double-blind

 

      nature of those two trials.  The first and foremost

 

      is geography, namely, that one study was conducted

 

      in Europe and Asia and the other in North America,

 

      and practice issues may pertain.

 

                Secondly, although SPORTIF V patients more

 

      often had hypertension, their blood pressures were

 

      6 mm mercury lower, on average, than patients in

 

      SPORTIF III.

 

                And, third, there was an artificially

 

      intense control of INRs in SPORTIF V relative to

 

      SPORTIF III, because in SPORTIF III there were over

 

      270 clinical laboratories conducting INR

 

      measurements, but there were essentially two in

 

      SPORTIF V, achieving some kind of standardization

 

      that is difficult to quantify.

 

                                                                85

 

                Another aspect that is important to

 

      consider is that the ximelagatran rates were

 

      identical in the two trials.  And in the warfarin

 

      trials--I'm sorry, in the two trials, the

 

      ximelagatran rates were identical, about 1.6.  The

 

      warfarin rates appear disparate.  But those rates

 

      are actually within the range of rates that are

 

      seen in prior stroke prevention trials.

 

                What we may be looking at here is another

 

      manifestation of the variability of warfarin.  This

 

      slide shows in yellow the warfarin rates from the

 

      six index trials, in orange the two rates from the

 

      SPORTIF trials, and in dark brown the meta analysis

 

      rate for the trials in yellow.  And as you can see,

 

      the SPORTIF rates are within the range of the

 

      warfarin rates from the previous trials.

 

                I hope that gives some perspective.

 

                DR. FLEMING:  Could you put that slide up

 

      again?  Can I follow up?

 

                DR. BORER:  Sure.  Let me just put some

 

      ground rules here, though.  Steve has highlighted

 

      what will be one of the key issues for discussion

 

                                                                86

 

      later on, and rather than get into it in great

 

      detail here and get bogged down for the next hour,

 

      perhaps we can deal only with issues of fact, and

 

      then we'll get into the evaluation of those facts a

 

      little bit later.

 

                But with that in mind, go ahead, Tom.

 

                DR. FLEMING:  If you could put that slide

 

      up, I just think for clarification, I don't think

 

      that the point you just raised really answered

 

      Steve's question.  Steve's question had more to do

 

      with the heterogeneity in the relative risk

 

      estimate across to pivotal studies.  This is

 

      getting at the heterogeneity of the control arm

 

      event rates across trials.  And, in fact, those are

 

      different phenomenon.  This really gets at the

 

      unreliability of noninferiority comparisons because

 

      of this tremendous heterogeneity, which is a

 

      separate issue.

 

                While I have the mike, could I ask a

 

      question that I had in mind?  That is, one of the

 

      things that's always concerned me in trials with

 

      venograms is that we end up with a lot of missing

 

                                                                87

 

      data, far more than what this committee would be

 

      used to accepting in a manner to maintain integrity

 

      of randomization.  I think you had 20 and 15

 

      percent, respectively, missing the outcome

 

      assessments in EXULT A and EXULT B.

 

                With that in mind, and also wanting to

 

      really focus on what are not surrogates but true

 

      clinical endpoints, endpoints that reflect tangible

 

      benefit to patients, I struggle to look for what

 

      are those measures that are really tangible that

 

      are measured uniformly in patients.  Could you show

 

      Slide CE-19 as we look at EXULT A and B?  Two of

 

      these measures are pulmonary embolism and death

 

      that should be assessed, I'm assuming, and

 

      available in all patients.  Your survival figures

 

      here reflect, if I pool here, five deaths against

 

      three.  The agency on page 26 of their briefing

 

      document has ten against four, so you're missing

 

      five deaths in the Exanta arm and one in the

 

      warfarin arm.  Could you clarify that discrepancy?

 

                DR. HORROW:  If I may first address the

 

      issue of the heterogeneity, then we can go on to

 

                                                                88

 

      the issue with EXULT.

 

                If I'm not mistaken, you're referring, in

 

      terms of the heterogeneity in SPORTIF, to what may

 

      be called a study by treatment interaction, the

 

      difference in sampling and getting one set versus

 

      the other.  And I think it's important to

 

      understand that in each case, noninferiority was

 

      satisfied; that is, looking at the data just in

 

      those terms and how those numbers are sorted does

 

      not take into account the noninferiority design of

 

      the trials and that the success is determined by

 

      whether or not it meets the noninferiority

 

      criterion.

 

                The heterogeneity result which we've

 

      looked at is not robust to sensitivity analyses

 

      like the primary results are robust.  So, for

 

      example, if one looks at primary events plus

 

      all-cause mortality, which was an endpoint

 

      suggested by the agency, the heterogeneity

 

      disappears and the p value is 0.23.  And if you

 

      look at other prespecified outcomes, such as major

 

      bleeding, there's no suggestion of disparity there.

 

                                                                89

 

      The heterogeneity p value is 0.81.  For total

 

      bleeding it's 0.275.

 

                And so we view the idea of disparate

 

      results in the two trials with some suspicion and

 

      think that we need to be very careful how we

 

      interpret those primary results in terms of being

 

      disparate or the same.  We view them as sampling

 

      from the same pool and getting two separate results

 

      and that the best estimate of the data comes from

 

      pooling.

 

                I'd like now to--

 

                DR. FLEMING:  Given that you didn't answer

 

      my question and you provided a different answer,

 

      let me respond to the answer you just gave.  The

 

      question that Steve asked is why was there such

 

      heterogeneity in relative risk estimates.  The

 

      answer that you gave was there's a lot of

 

      heterogeneity in the control arm, in the warfarin

 

      rates across trials.  Logically, I would assume

 

      that if you're saying when the warfarin rate in

 

      truth is different across trials, we should expect

 

      a different treatment effect, it really makes me

 

                                                                90

 

      worry about doing a noninferiority trial where you

 

      have to rely on historical evidence.

 

                Could you answer, though, the question

 

      that I'd asked here about the discrepancy between

 

      your data here and the FDA briefing document?

 

                DR. HORROW:  I'd like to ask Dr. Scott

 

      Berkowitz, who was the medical person for this

 

      particular trial, to address this issue.

 

                DR. BERKOWITZ:  Yes, Scott Berkowitz,

 

      AstraZeneca.  I just wanted to say in terms of the

 

      venography rate--I have the data to show you, but

 

      in terms of venograph, these two trials had the

 

      highest adequacy of evaluability ever done in

 

      clinical trials for pivotal purposes.

 

                DR. FLEMING:  That may be, and yet the

 

      reality is we're still lacking 15 to 20 percent of

 

      our randomization cohort, and we no longer are

 

      assured of integrity of randomization.  So could I

 

      get the answer to my question?

 

                DR. BERKOWITZ:  So for what you saw, those

 

      data that you saw in the briefing packet were for

 

      the overall study, so you can see it's ten and

 

                                                                91

 

      four, but I'm going to--could I have the next

 

      slide?--show you the breakout for treatment, which

 

      is the primary endpoint--

 

                DR. FLEMING:  So, in fact, what I do want

 

      is the entire study, ten and four.  So is the

 

      clarification CE-19, then--

 

                DR. BERKOWITZ:  Could we go back?

 

                DR. FLEMING:  Then the reason CE-19 is

 

      leaving out the five deaths and one death is that

 

      those occurred in the non-80, 85 percent?

 

                DR. BERKOWITZ:  The deaths--I'm sorry.

 

      Say that again?  I'm sorry.

 

                DR. FLEMING:  What is the reason that your

 

      slide here leaves out five deaths and one death?

 

                DR. BERKOWITZ:  That slide showed the

 

      primary endpoint which included the treatment

 

      period of day 7 to 12 days as opposed to the

 

      overall, which showed only this study and the next

 

      one, if you want to see the breakout.

 

                DR. FLEMING:  Good.  And so that is--could

 

      you show it again?

 

                DR. BERKOWITZ:  Oh, yes.  Can I see the

 

                                                                92

 

      next one?  Thank you.  We want to see now the

 

      breakout between the treatment--

 

                DR. FLEMING:  So that the total deaths are

 

      as here, they are as there in the FDA briefing

 

      document, ten against four in the wrong direction.

 

      And pulmonary embolism is, according to the FDA

 

      briefing document, four against five as reported by

 

      the FDA.

 

                DR. BERKOWITZ:  Yes.  Well, you can see

 

      down--for the treatment period, as you can see,

 

      there was one in the ximelagatran 36 group and none

 

      in warfarin.  During the follow-up period, there

 

      were four in the ximelagatran group and zero in

 

      warfarin.

 

                DR. FLEMING:  And so in an ITT analysis

 

      that does include all patients and focuses on,

 

      among the most clinically relevant endpoints, death

 

      and pulmonary embolism, it appears that there are

 

      actually numerically an excess of events in the

 

      Exanta group.  By my count there are 15 events

 

      against 10 events, and that's your numbers as well.

 

      Is that correct?

 

                                                                93

 

                DR. BERKOWITZ:  Well, except that the

 

      numbers that you're seeing in follow-up are after

 

      patients are off treatment but they get seen in 4

 

      to 6 weeks.

 

                DR. FLEMING:  I want ITT, and that's what

 

      it looks like.  Is that correct?  It's 15 against

 

      10 in the wrong direction?  Just is the FDA summary

 

      correct on page 26?

 

                DR. BERKOWITZ:  Yes.

 

                DR. FLEMING:  And one other quick

 

      question, if I could.  Again, wanting to try to

 

      focus on an ITT of a critical endpoint, all-cause

 

      mortality, in THRIVE III could you show us the ITT

 

      summary?  This is the placebo-controlled trial

 

      where we see a substantial efficacy result on the

 

      symptomatic endpoint.  Could you show us the ITT of

 

      the survival curves for that trial?

 

                DR. BERKOWITZ:  I'm not certain--did you

 

      want to see the slide that we showed for the

 

      original presentation?

 

                DR. FLEMING:  I believe it's corresponding

 

      to the page 7, Figure 1 in your briefing document.

 

                                                                94

 

                DR. BERKOWITZ:  Let me bring that up.  I

 

      just want to be sure it's the same one that we saw.

 

                DR. FLEMING:  The one that I am in

 

      particular looking for here, because that figure

 

      includes all the data from all the trials, is in

 

      particular THRIVE III with ITT analysis of

 

      mortality over the time frame that you followed

 

      these patients.

 

                DR. BERKOWITZ:  Yes, okay, and that's what

 

      we were--yes, I'm sorry.  So here you go.  This is

 

      the slide.

 

                DR. FLEMING:  Mortality.

 

                DR. BERKOWITZ:  Yes.

 

                DR. FLEMING:  All-cause, ITT.

 

                DR. BERKOWITZ:  I'm sorry.  I still don't

 

      understand what you--just the mortality slide?

 

                DR. FLEMING:  Yes, as you have in Figure 1

 

      of your briefing document.

 

                DR. BORER:  You wanted to see only for

 

      THRIVE, or you wanted to for the--

 

                DR. FLEMING:  Either way, if you--okay.

 

                DR. BERKOWITZ:  This is the slide in the

 

                                                                95

 

      briefing document that you're speaking of with all

 

      the mortality.

 

                DR. FLEMING:  Okay.  And could you--so the

 

      THRIVE is, in fact, the--

 

                DR. BERKOWITZ:  I'm sorry, yes, the THRIVE

 

      is the lowest curve there, the ximelagatran versus

 

      placebo in the lowest group.

 

                DR. FLEMING:  And so essentially, while

 

      I'm focusing on THRIVE, the evidence here would

 

      suggest, even in placebo-controlled comparisons,

 

      there's strong suggestion of no differences in

 

      survival.

 

                DR. BERKOWITZ:  Well, I mean, they're

 

      lower with the ximelagatran group, but not a strong

 

      difference.

 

                DR. FLEMING:  I'm sorry.  I don't--the

 

      curves look overlapping in the THRIVE III, and in

 

      the other studies they are very overlapping as

 

      well.

 

                DR. BORER:  Steve?

 

                DR. NISSEN:  Yes, I just had one more

 

      question, still trying to probe to understand the

 

                                                                96

 

      differences between SPORTIF III and SPORTIF V.

 

      Could you show us the INR values, that is, the

 

      degree of anticoagulation control in SPORTIF III

 

      and SPORTIF V for the warfarin arms.

 

                DR. BERKOWITZ:  I'll ask Dr. Jay Horrow to

 

      present that.

 

                DR. HORROW:  I'm sorry.  I missed the last

 

      two words in--

 

                DR. NISSEN:  Yes, I just want to see in

 

      the warfarin arm of the trials, I want to see what

 

      the INRs looked like in SPORTIF III and SPORTIF V.

 

                DR. HORROW:  Okay.  I believe these data

 

      will address your question.  There were almost

 

      100,000 different INR values, and this summary

 

      perhaps helps.  Here we have SPORTIF III and

 

      SPORTIF V and the percentage of time in specific

 

      ranges.

 

                DR. NISSEN:  It does.

 

                DR. HORROW:  Okay.  Thank you.

 

                DR. BORER:  A final question of fact,

 

      Jonathan?

 

                DR. SACKNER-BERNSTEIN:  I think the key

 

                                                                97

 

      thing is that all of the slides that show ITT are

 

      not true ITT analyses.  It's not just THRIVE.  It's

 

      THRIVE and EXULT, and they list that in the

 

      briefing document.  There are a lot of numbers

 

      where those are different, so we should just

 

      interpret it that way.

 

                DR. FLEMING:  It was part of the reason

 

      for my asking the question.  I wanted to get a

 

      verification that we were being shown, for

 

      endpoints such as mortality, a true ITT.  And I

 

      understand that they're telling us they are showing

 

      us a true ITT where you have uniform follow-up

 

      through a given calendar date at which the study

 

      data freeze would have occurred, and you would have

 

      complete follow-up on mortality for all patients.

 

      Is that what that Figure 1 showed?

 

                DR. HORROW:  Yes.

 

                DR. BORER:  Okay.  Thank you, Jay.

 

                DR. HORROW:  May I introduce Dr. Sunita

 

      Sheth, who will discuss particular aspects of

 

      safety for ximelagatran.

 

                DR. SHETH:  Good morning.  I'm Sunita

 

                                                                98

 

      Sheth, Senior Director of Clinical Research at

 

      AstraZeneca.

 

                You've just seen the efficacy data

 

      supporting the benefit of ximelagatran as an oral

 

      anticoagulant.  I'll now review the clinical safety

 

      date.  The analysis comes from a large data set

 

      with more than 30,000 subjects, many of the

 

      patients involved having serious underlying disease

 

      and receiving multiple drug therapy.

 

                First, I'll discuss by indication the

 

      adverse events and bleeding profiles.  Efficacy for

 

      any anticoagulant is balanced by risk of bleeding.

 

      Indeed, bleeding and the prevention of thrombosis

 

      derive from the same action of drug.  That's why

 

      bleeding was a prespecified endpoint in the pivotal

 

      trials.  And major bleeding was adjudicated in a

 

      blinded fashion in all Phase II and Phase III

 

      trials.  Then I'll focus on two specific topics:

 

      myocardial ischemic events and the hepatic

 

      findings.  Finally, I'll conclude with a review of

 

      overall mortality and summarize the key points for

 

      each indication.

 

                                                                99

 

                It may help if I display how we've

 

      organized the large data set.  It divides logically

 

      into three groups:  Phase I, surgical, and

 

      nonsurgical populations.  The Phase I population,

 

      composed primarily of healthy volunteers dosed for

 

      up to 8 days, didn't present any safety signals.

 

      Surgical patients, mostly from the orthopedic

 

      studies with dosing up to 12 days, have different

 

      safety issues, in particular, perioperative

 

      bleeding, and so they are reviewed as a separate

 

      group.

 

                The nonsurgical population primarily

 

      received drug for more than 35 days and provides

 

      the core safety evaluation of long-term dosing,

 

      with exposure up to 4 years.  Each population pool

 

      is large, allowing a detailed assessment of safety

 

      in each case.

 

                I will first review the safety for the

 

      surgical indication.  The North American surgical

 

      population has been termed "the warfarin comparison

 

      pool" and provides the safety data for the

 

      indication under consideration today, with

 

                                                               100

 

      post-operative dosing of either oral ximelagatran

 

      or warfarin after total knee replacement surgery.

 

      This pool includes data from three Phase III

 

      trials:  the two EXULT trials as well as an earlier

 

      study evaluating 24 milligrams versus warfarin.

 

      Overall, it includes 5,236 patients.

 

                In all graphs, ximelagatran will be shown

 

      in a shade of orange and the comparator in gray.

 

                Here's the summary of adverse events for

 

      the surgical pool.  Both treatment groups showed a

 

      similar frequency and type of adverse events.

 

      There didn't appear to be any dose response

 

      comparing the 24- and 36-milligram doses.  We can

 

      look more closely at the EXULT trials where both

 

      major and minor bleeding events underwent

 

      independent adjudication.  Rates of major bleeding,

 

      shown at the bottom of each bar, were 1 percent or

 

      less in all treatment groups, with no statistically

 

      significant differences for major bleeding alone or

 

      for the combination of major and minor bleeding,

 

      for which respective p values are shown.

 

                When you look at the data for the proposed

 

                                                               101

 

      36-milligram dose, there wasn't a difference in

 

      surgical outcome parameters, such as wound hematoma

 

      or intra-articular bleeding.  Additionally, the

 

      proportion of patients receiving transfusion and

 

      the volume of transfusion were similar in each

 

      group.

 

                Now, let me turn to the nonsurgical

 

      patients who comprise the long-term dosing group.

 

      This group is called the long-term exposure or LTE

 

      pool, with patients from all the Phase II and Phase

 

      III studies conducted so far involving dosing

 

      beyond a month's duration.  In addition to patients

 

      from the atrial fibrillation and venous

 

      thromboembolic secondary prevention indications,

 

      we've included data from two other disease areas

 

      where significant trials have been conducted,

 

      patients undergoing initial 6-month treatment for a

 

      venous thromboembolic event and patients post-acute

 

      coronary syndromes.  The overall ximelagatran

 

      exposure is substantial, a total of 6,768 patient

 

      years, with a median exposure of 370 days.

 

                Across this population, doses between 20

 

                                                               102

 

      and 60 milligrams have been used, although the

 

      majority of patients, 75 percent of them, received

 

      36 milligrams twice daily.  The comparator group

 

      includes both placebo as well as warfarin and is

 

      termed "the comparators' group."  In this group, 20

 

      percent of patients received placebo.

 

                I'll now comment on the different

 

      indication pools.

 

                In the VTE extended prophylaxis pool, both

 

      ximelagatran and placebo groups demonstrate similar

 

      frequency and types of adverse events.  The

 

      incidence of serious adverse events and

 

      discontinuations was actually lower in the

 

      ximelagatran group compared to placebo.

 

                In the same group, major bleeding occurred

 

      rarely, affecting six patients in the ximelagatran

 

      group and five patients in the placebo group.

 

      Ximelagatran and placebo groups also did not differ

 

      with respect to major or minor bleeding events.

 

                In the atrial fibrillation pool, the same

 

      frequency and types of adverse events were recorded

 

      in both the ximelagatran and warfarin groups. 

 

                                                               103

 

      Discontinuations were higher in the ximelagatran

 

      group, not because of symptoms but mainly due to a

 

      protocol-mandated discontinuation for ALT

 

      elevation.  I'll discuss this in detail shortly.

 

                In the atrial fib population, the rates of

 

      major bleeding with ximelagatran did not differ

 

      from those with warfarin.  Minor bleeding events

 

      occurred quite often in these trials and for that

 

      reason did not undergo adjudication.  Here we see

 

      the event rates for patients with one or more major

 

      or minor bleeding events.  Total bleeding occurred

 

      significantly less often with ximelagatran than

 

      with warfarin, with a p value of less than 0.001.

 

                Overall, with regard to adverse events and

 

      bleeding, ximelagatran compared to well-controlled

 

      warfarin following total knee replacement surgery,

 

      compared to placebo and extended secondary

 

      prophylaxis of VTE, and compared to warfarin in

 

      atrial fibrillation patients demonstrated no

 

      important differences in adverse events, bleeding

 

      profile, or the safety profile of the 24- and

 

      36-milligram doses.  In addition, a detailed

 

                                                               104

 

      subgroup analysis for bleeding supports the

 

      proposed fixed-dose approach for all types of

 

      patients studied.

 

                I'll now review two special safety topics,

 

      coronary artery disease and the hepatic findings.

 

      First let's address the coronary artery disease

 

      findings.

 

                The agency has noted a possible imbalance

 

      in the frequency of myocardial infarctions.  Shown

 

      here is Table 12 from the FDA briefing document.

 

      The events shown here are investigator-reported

 

      events.  Note that the absolute number of

 

      myocardial infarctions observed in the EXULT trials

 

      was small, and there appears in a post-hoc analysis

 

      to be a significant difference with a p value of

 

      0.049.  However, this difference is driven by a

 

      single trial, EXULT A.  Furthermore, an analysis of

 

      other coronary artery disease events failed to

 

      reveal any significant difference.

 

                FDA Table 40 shows investigator-reported

 

      coronary adverse events from selected trials from

 

      the long-term pool.  This analysis suggested an

 

                                                               105

 

      increased frequency of total coronary adverse

 

      events in the VTE treatment population.  When VTE

 

      treatment and extended prophylaxis are evaluated I

 

      a post-hoc pooling and analysis, the p value is

 

      significant for both myocardial infarctions and

 

      other coronary artery disease events.  However,

 

      this finding was not observed in the much larger

 

      atrial fibrillation pool.  In addition, the trial

 

      in acute post-coronary syndromes where benefit was

 

      demonstrated is not included in this analysis.  In

 

      fact, when all three groups are pooled, no

 

      significant difference is observed for either

 

      myocardial infarctions or other coronary events.

 

                In addition to the investigator-reported

 

      events, the SPORTIF trials in atrial fibrillation

 

      with an active comparator, warfarin, and the ESTEEM

 

      trial in the post-ACS setting versus placebo

 

      provided an independent and objective assessment of

 

      myocardial infarctions.  In fact, adjudicated

 

      events in these trials represent over 90 percent of

 

      all MIs across the program.  Here, evaluation of

 

      the SPORTIF trials demonstrated an identical

 

                                                               106

 

      incidence while the ESTEEM trial demonstrated an

 

      actual reduction in myocardial infarctions.

 

                It is also relevant in this context that

 

      across the whole program we have no evidence of any

 

      rebound effects producing MIs after ximelagatran

 

      treatment was stopped.

 

                So with regard to coronary artery disease

 

      adverse events, while a concern was raised

 

      regarding a potential imbalance in events, a more

 

      comprehensive analysis focusing on both

 

      investigator-reported and objectively assessed

 

      events fails to identify an increased risk.

 

                I now want to turn to the unexpected

 

      results, the hepatic findings, and present a

 

      detailed review.

 

                We've taken the findings very seriously,

 

      and from the large database individual case

 

      analysis and consultation with hepatic experts,

 

      we've produced a thorough assessment.  I'll first

 

      review the laboratory findings followed by the

 

      adverse event data.

 

                Preclinical toxicology and the Phase I

 

                                                               107

 

      studies did not demonstrate any hepatic safety

 

      issue.  The surgical studies with up to 12 days of

 

      dosing didn't show any hepatic changes with

 

      ximelagatran, just the well-recognized enzyme

 

      elevation seen with heparin.  In the first Phase II

 

      long-term dosing study with ximelagatran in the

 

      atrial fibrillation patients, a signal of an

 

      asymptomatic increase in ALT greater than 3 times

 

      the upper limit of normal was noted.  Therefore,

 

      the standard laboratory testing that was being

 

      performed early in the development program was

 

      increased in the Phase III studies.

 

                The liver function testing panel consisted

 

      of alanine amino transferase, or ALT; aspartate

 

      aminotransferase, or AST; alkaline phosphatase, and

 

      total bilirubin.  These tests were performed

 

      monthly for the first 6 months of exposure, then

 

      every 2 months up to one year, and then quarterly.

 

      In addition, weekly testing and discontinuation

 

      criteria were defined.  These criteria were

 

      strengthened after one case of biopsy-documented

 

      hepatic necrosis.

 

                                                               108

 

                As mentioned, there was no increase in ALT

 

      greater than 3 times the upper limit of normal in

 

      ximelagatran patients undergoing total knee

 

      replacement compared to warfarin during treatment.

 

      At the 4- to 6-week follow-up, there were eight

 

      patients in the ximelagatran group and three in the

 

      warfarin group that developed an increase in ALT.

 

      In general, these increases occurred 3 weeks after

 

      discontinuation of drug.  It's important to note

 

      that two patients with the transaminase elevation

 

      in follow-up in the ximelagatran group had received

 

      low-molecular-weight heparin.  The ALT elevation in

 

      all patients but one in each group is documented as

 

      resolved.  We believe that patients undergoing

 

      orthopedic surgery with short-term dosing of

 

      ximelagatran are not at an increased risk of ALT

 

      elevations or liver injury.

 

                Now, let me summarize the incidence of

 

      enzyme elevations of the long-term exposure pool.

 

      The incident of ALT greater than 3 times the upper

 

      limit of normal was 7.9 percent for ximelagatran

 

      compared with 1.2 percent for comparators.  It's of

 

                                                               109

 

      interest to note that there was no difference

 

      between groups for isolated elevations of

 

      bilirubin.  The vast majority of these enzyme

 

      elevations were asymptomatic.

 

                Our experience shows that the time

 

      signature for ALT elevation follows a consistent

 

      pattern.  This graph depicts the number of patients

 

      with first ALT greater than 3 times the upper limit

 

      of normal over time.  The y axis represents the

 

      cumulative risk of an ALT greater than 3 times the

 

      upper limit of normal and the x axis time in

 

      months.  As can be seen, the occurrence increases

 

      above background rates after 1 month and approaches

 

      background rates after 6 months.  Ninety-three

 

      percent were detected during the first 6 months,

 

      and 98 percent within the first 12 months.

 

                I now want to turn to the disposition of

 

      patients with an ALT increase.  Of the 546 patients

 

      in the ximelagatran group that had an increase to

 

      greater than 3 times the upper limit normal, 46

 

      percent of patients continued to treatment and

 

      completed the study.  The other 54 percent

 

                                                               110

 

      discontinued study drug.  Overall, 96 percent of

 

      ximelagatran-treated patients returned to less than

 

      or equal to 2 times the upper limit of normal ALT,

 

      regardless of continuation or discontinuation of

 

      drug.  Of the 74 patients in the comparator group,

 

      31 percent continued treatment, and the other 69

 

      percent discontinued treatment.  Overall, 93

 

      percent of comparator-treated patients recovered.

 

                The algorithm allows continuation of

 

      treatment for mild and transient increases on drug.

 

      These data demonstrate the reversibility of the ALT

 

      increases.

 

                Patients who continued drug recovered by a

 

      median of 28 days, and those who discontinued drug

 

      by a median of 40 days.  Eighteen patients were

 

      rechallenged early in the program.  Only two

 

      patients had a subsequent ALT rise.  One pt with a

 

      peak ALT of 10 times the upper limit of normal was

 

      rechallenged after 65 days and did not have a

 

      repeat elevation until 2 months later.  The second

 

      peak was at 3 times the upper limit of normal, and

 

      the drug was discontinued.

 

                                                               111

 

                The second patient did not have a true

 

      rechallenge, but had multiple episodes above 3

 

      times the upper limit of normal, but overall

 

      recovered with continuation of the drug.  There was

 

      no evidence in these or any other patients for an

 

      immunoallergic response.

 

                Hepatic experts that we consulted

 

      suggested that the elevation of ALT greater than 3

 

      times the upper limit of normal and clinical

 

      jaundice, in the absence of an alternative

 

      diagnosis, can be considered a signal of severe

 

      hepatic injury.  We selected a more conservative

 

      definition to standardize the levels and timing and

 

      included cases with ALT greater than 3 times the

 

      upper limit of normal and bilirubin greater than 2

 

      times the upper limit of normal, the latter

 

      occurring within one month of the ALT rise.

 

                A total of 37 patients, or 0.53 percent,

 

      in the ximelagatran group had this concurrent

 

      elevation of ALT and bilirubin, compared with five

 

      patients in the comparators' group, with an

 

      incidence of 0.08 percent.

 

                                                               112

 

                Please note that one additional case has

 

      been included in this analysis at the request of

 

      the FDA.  We had fully documented this case

 

      involving a fatal GI bleed in the submission and

 

      had also highlighted it as a case of interest in

 

      the safety review.

 

                I'll now review the outcome in patients

 

      with a concurrent increase in both ALT and

 

      bilirubin.  Confounding diagnoses were noted in 25

 

      of the 37 patients on ximelagatran.  Seven patients

 

      in the subset died of unrelated causes.  Twelve

 

      patients did not have an alternative diagnosis for

 

      the enzyme elevation.  Of these 12, two died with a

 

      GI bleeding event and will be discussed shortly.

 

      The ALT and bilirubin in all other patients

 

      recovered.  Of the five cases in the comparator

 

      group, four had an alternative diagnosis, and only

 

      one had an unexplained increase.  Two patients died

 

      from pancreatic cancer.  The other patients

 

      recovered.

 

                We have been investigating a possible

 

      mechanism for the hepatic changes, but so far this

 

                                                               113

 

      has not been elucidated.  Preclinical studies

 

      evaluating reactive metabolites, mitochondrial

 

      dysfunction, and protein binding have not been

 

      revealing.  There is no evidence for involvement of

 

      the P450 system.  The asymptomatic and

 

      nonprogressive pattern of ALT increase has been

 

      noted with other drugs, including tacrine, INH,

 

      amiodarone, among others.

 

                We wanted to understand if there's a

 

      subgroup that's at increased risk.  Because the

 

      number of patients with concomitant ALT and

 

      bilirubin is so low, this analysis was performed on

 

      the occurrence of ALT greater than 3 times the

 

      upper limit of normal.  Therefore, these results

 

      should be interpreted with caution.  A step-wise

 

      logistic regression was performed looking at

 

      demographic factors, statin use, and baseline

 

      disease.  As expected, the most significant factor

 

      in this analysis was ximelagatran treatment with an

 

      odds ration of 6.82.

 

                Other factors that demonstrated

 

      statistical significance all had an odds ratio of

 

                                                               114

 

      less than 2.  These includes patients post-ACS,

 

      patients being treated for an acute venous

 

      thromboembolic event, body mass index less than 25

 

      kilograms per meter squared, and female gender.

 

      Statins and creatinine clearance were not

 

      identified as significant factors.

 

                The variable of ALT greater than 3 times

 

      the upper limit of normal is generally asymptomatic

 

      and reversible.  Therefore, this analysis does not

 

      allow a prediction for those at risk for severe

 

      liver injury.  We are, therefore, recommending ALT

 

      testing for everyone who starts long-term treatment

 

      with ximelagatran.

 

                Now let's look at the adverse event data

 

      from these patients.  No difference is noted

 

      between groups for clinical hepatobiliary adverse

 

      events.

 

      T2B                      I will now briefly review

 

      three selected cases in the group of patients with

 

      concomitant increase in ALT and bilirubin

 

      associated with ximelagatran.  These cases were

 

      selected by the FDA as three deaths with associated

 

                                                               115

 

      severe liver injury.  The first two cases occurred

 

      on the first algorithm, and the third case on the

 

      second more conservative algorithm.  The second and

 

      third case did not demonstrate compliance with the

 

      algorithm in effect at the time.  The deaths in all

 

      three cases are also confounded by other factors.

 

                In the first two cases, the ALT and

 

      bilirubin increase was unexplained, and the

 

      terminal event in both cases was a GI bleeding

 

      event.

 

                The first patient, an 80-year-old male,

 

      had a hepatic biopsy with documented hepatic

 

      necrosis about 1 month before death.  This patient

 

      had evidence of decreased hepatic function.

 

      However, the ALT was recovering when he died from a

 

      perforated duodenal ulcer.  This patient had been

 

      on prednisone.

 

                The second case presented hypertensive to

 

      the hospital with an elevated ALT of 11 times the

 

      upper limit of normal and a bilirubin of 1.4 times

 

      the upper limit of normal after missing two weekly

 

      tests for an elevated ALT.  The INR was 3.4 and the

 

                                                               116

 

      APTT was 69 seconds.  His last dose of ximelagatran

 

      had been earlier that evening.  The patient had a

 

      prior history of duodenal ulcer and Bilroth II

 

      anastomosis with bleeding at the site detected on

 

      this admission.  During the 24 hours from the

 

      admission to death, the patient received massive

 

      transfusions.  During this time his bilirubin

 

      increased from 1.4 times the upper limit of normal

 

      to 9.4 times the upper limit of normal, with 50

 

      percent noted as indirect bilirubin.  At the time

 

      of death, the bilirubin was 7.3 times the upper

 

      limit of normal and the ALT less than 2 times the

 

      upper limit of normal.

 

                The third case was a death due to

 

      fulminant reactivation hepatitis B with an elevated

 

      ALT upon study initiation.  This patient was on two

 

      immunosuppressive drugs:  prednisone and

 

      azathioprine.  Ximelagatran was not discontinued

 

      when the ALT reached greater than 5 times the upper

 

      limit of normal as recommended.  The patient had a

 

      rapid and fulminant course attributed to the

 

      hepatitis B.  However, the investigator could not

 

                                                               117

 

      rule out that the drug did not contribute to the

 

      fulminant course.

 

                To summarize the hepatic findings, ALT

 

      elevations greater than 3 times the upper limit of

 

      normal occurred in 7.9 percent of

 

      ximelagatran-treated patients, occurring primarily

 

      within the first 6 months.  The elevations were

 

      typically asymptomatic and reversible, without any

 

      evidence of an immunoallergic reaction.  An

 

      incidence of 0.5 percent of concurrent ALT greater

 

      than 3 times the upper limit of normal and

 

      bilirubin greater than 2 times the upper limit of

 

      normal was observed.  Exposure response suggests

 

      that exposure is not predictive of individual risk

 

      of transaminase elevation, and no patient subset

 

      was identified to be at higher risk of developing

 

      severe hepatic injury.

 

                Based on the data, we are proposing ALT

 

      testing in the label reflecting the more

 

      conservative testing schedule used in clinical

 

      trials.  To make sure that ALT testing becomes the

 

      standard of care with ximelagatran, we also

 

                                                               118

 

      submitted a risk minimization plan which set out

 

      our initial proposals to support ALT testing in

 

      practice.  This proposal was developed after

 

      extensive external consultation and field testing,

 

      but we recognize that it may need to be developed

 

      further in the best interests of ensuring patient

 

      safety.  We have a meeting arranged with FDA on

 

      this topic in the near future.

 

                A few comments on the principles of our

 

      Risk Minimization Action Plan.  The ultimate goal

 

      of the plan is to prevent any hepatic failure

 

      caused by treatment with ximelagatran.  To do this,

 

      the Risk MAP will help to ensure compliance with

 

      labeled ALT testing recommendations.  This proposal

 

      was developed to provide access to ximelagatran by

 

      those patients who will benefit while minimizing

 

      risk.  It targets patients, physicians, and

 

      pharmacists.  It has a strong educational focus and

 

      is enhanced with practice management tools and

 

      special packaging.  In addition, following

 

      discussions with FDA, AstraZeneca will be proposing

 

      additional enhancements to ensure our ALT testing

 

                                                               119

 

      recommendations are followed.  Finally, we have

 

      proposed continuous evaluation of program

 

      effectiveness.

 

                AstraZeneca understands that the full

 

      benefit of ximelagatran can only be realized if it

 

      is used in accordance with the labeled recommendations, and

 

      to that end we are committed to

 

      developing the specifics of the program in

 

      consultation with the agency.

 

                To complete the assessment of safety, we

 

      will finish with the overall mortality in the

 

      long-term exposure pool to get an overview of risk.

 

      The patient population was primarily an elderly

 

      population with multiple comorbidities and

 

      concurrent medications.  Despite an increase in ALT

 

      in the ximelagatran-treated patients, no difference

 

      in all-cause mortality was noted.  Mortality was

 

      similar in the ximelagatran group compared to

 

      patients on placebo, patients on placebo plus

 

      aspirin, and patients on warfarin.

 

                Let me finish by summarizing the

 

      benefit/risk comments for each indication. 

 

                                                               120

 

      Ximelagatran prevented venous thromboembolism

 

      and/or all-cause mortality compared with warfarin

 

      in total knee replacement surgery with a number

 

      needed to treat of 12.  No difference was seen in

 

      bleeding, transfusions, or surgical outcome.

 

                Ximelagatran demonstrated clear benefit

 

      over placebo with a number needed to treat of 10 in

 

      the long-term prevention of recurrent VTE events.

 

      This included a clinically important reduction in

 

      pulmonary embolus, a condition that can result in

 

      serious morbidity and mortality.  The incidence of

 

      bleeding was comparable to placebo.

 

                Ximelagatran was as effective as warfarin

 

      in reducing the risk of stroke and other

 

      thromboembolic events in patient with atrial

 

      fibrillation.  Bleeding was lower on ximelagatran.

 

      With regards to the hepatic findings, while the

 

      risk per year for stroke or venous thromboembolism

 

      is continuous, the risk for an ALT rise and

 

      subsequent severe liver injury is limited primarily

 

      to the first 6 months of ximelagatran therapy.  But

 

      the protection from a thrombotic event by

 

                                                               121

 

      ximelagatran is continuous and consistent over

 

      time.

 

                To aid effective management of the hepatic

 

      risk, ALT testing will be recommended in our

 

      proposed labeling, and in addition, we have

 

      submitted a Risk Minimization Action Plan which we

 

      will discuss further with the FDA.

 

                We conclude that ximelagatran, the first

 

      new oral anticoagulant in over 50 years, does have

 

      a positive benefit/risk in each proposed indication

 

      provided that the drug is used properly.  We look

 

      forward to your comments and further dialogue with

 

      the agency.

 

                Thank you.  I'll take questions.

 

                DR. BORER:  Dr. Sheth, I think we need to

 

      take a break.  I've been chastised when we haven't

 

      done that.  So we'll take a 10-minute break, and

 

      then we'll go on to the questions of fact about the

 

      safety data, and I think we can then go on to

 

      Jonathan Halperin's presentation, and we'll just

 

      make up the remaining FDA time after the public

 

      comments later so that you can get your whole

 

                                                               122

 

      presentation in.

 

                So we'll take a 10-minute break right now.

 

      Look at your watch because 10 minutes from now

 

      we're going to start again.

 

                [Recess.]

 

                DR. BORER:  While everybody is getting

 

      back in here and sitting down--or not sitting

 

      down--let me raise an issue for you to begin to

 

      think about as people are coming back in.

 

                Steve Nissen asked earlier about

 

      pharmacological evidence of rebound, and there

 

      didn't appear to be significant rebound, although I

 

      don't know what that means in the context of

 

      studies with limited power.  But there didn't seem

 

      to be significant rebound of pharmacological

 

      effects, although the follow-up, as I recall, was

 

      relatively short.  So we don't know about late

 

      pharmacological changes.  But as I look at these

 

      data from each of the trials, I'm struck with a

 

      difference between the on-treatment and

 

      post-treatment frequency of major adverse

 

      cardiovascular events that I'd like to hear some

 

                                                               123

 

      discussion about from you.  Is this real or is it

 

      not?  That is that if you look at the number of

 

      myocardial infarctions or other cardiac events that

 

      occurred on ximelagatran versus the comparator, the

 

      numbers were different but not all that different.

 

      It depended on the trial.  It varied from trial to

 

      trial, and we can talk about that potential adverse

 

      event disparity later.  But I'm concerned or I want

 

      to ask about something else.

 

                If you look at the number of events that

 

      occurred on-treatment, the numbers were relatively

 

      close one way or the other from trial to trial to

 

      trial.  If you look at the numbers that occurred

 

      post-treatment, the proportion of patients who had

 

      events on ximelagatran in the post-treatment period

 

      was greater as a percentage of the whole than was

 

      the case for any of the comparators.  The

 

      post-treatment events on warfarin or on placebo

 

      were fewer as a proportion of the whole of the

 

      total number of events in those comparator groups

 

      than was the case with ximelagatran, and in some

 

      cases the post-treatment events were more frequent

 

                                                               124

 

      than the on-treatment events with ximelagatran.

 

      That's an observation.

 

                Have you noted that?  And is that true?

 

      And do you have anything to say about it?

 

                DR. SHETH:  The numbers differ a little

 

      bit between the different patient groups.  So let

 

      me start first with the long-term exposure pool and

 

      some of the specific populations within that pool.

 

                If we can take a look again at the--and

 

      we're talking coronary events, Dr. Borer?

 

                DR. BORER:  Yes, we can limit it to

 

      coronary events, however they're defined.

 

                DR. SHETH:  What you see is that, you're

 

      right, there is a difference--I'm sorry.  Let's put

 

      that up.  You do see an increase--and these are

 

      both myocardial infarctions and total other

 

      coronary artery disease events other than MI

 

      compared in the VTE treatment and the VTE extended

 

      prophylaxis compared to warfarin.  But these

 

      numbers are actually quite small.  We're talking

 

      about a total of 16 patients here, 3, 16, 10, et

 

      cetera, versus 1, 0, 12, 3.

 

                                                               125

 

                If we take a look at two populations where

 

      you might say that the risk is actually increased,

 

      the atrial fib group had higher incidence of both

 

      diabetes, hypertension, for example.  You don't see

 

      that--those events, again, plus that in the

 

      post-acute coronary syndrome population, which is

 

      certainly a high-risk group for events.  Can we

 

      take a look at the next slide?  I'll come back to

 

      the after-treatment in a second.

 

                Ninety percent of the MIs--and this was

 

      during the trials--occurred in these two settings,

 

      and you don't see a difference there, and you see a

 

      benefit on treatment with ximelagatran.

 

                But if we take a look, let's say, at the

 

      post-acute coronary syndrome population, again, a

 

      higher-risk group, after treatment stopped, the

 

      incidence between those two groups was about 1.5

 

      percent--I think it's about 1.5 percent in both

 

      groups.

 

                DR. BORER:  Okay.  I'm sure you're right,

 

      and the data you just showed I think are very

 

      reassuring, and I think we all saw them in the book

 

                                                               126

 

      here.  But, again, I'm making a slightly different

 

      point, and maybe the data aren't available or

 

      aren't sufficient to draw a firm conclusion about

 

      them.

 

                What I am talking about is the proportion

 

      of coronary events that occurred after stopping

 

      treatment on ximelagatran as a percentage of the

 

      total number of events compared with the portion

 

      that occurred after stopping treatment with

 

      warfarin or placebo as a percentage of the total

 

      number of events in those groups.  I believe that

 

      the proportion of events that occur post-treatment

 

      is higher in the ximelagatran groups across all the

 

      trials, if you look at trial after trial, than is

 

      the case for the comparators, which raises some

 

      question about the possibility of a rebound

 

      phenomenon or something else, some other

 

      pathophysiological process that's being allowed to

 

      happen or occurring because of the use of the drug

 

      once it's stopped.

 

                DR. SHETH:  I understand what you're

 

      asking.  We don't have that specific analysis, so I

 

                                                               127

 

      won't be able to address it at this moment.  You're

 

      asking for those proportions of patients after they

 

      stop treatment over the total number of events, and

 

      right now I don't have that analysis.

 

                DR. BORER:  Okay.  You can pull it

 

      together later, but it's in the books.  If you look

 

      at the data that are presented, if you look at the

 

      numbers, that sort of jumps out at you.  So you may

 

      want to look at that, and you can talk about it

 

      after lunch or something.

 

                DR. SHETH:  Okay.

 

                DR. BORER:  Okay.  Well, why don't we go

 

      on and see--Alan?

 

                DR. HIRSCH:  Well, just one comment to

 

      follow up Jeff, and if you're able to provide that

 

      after lunch, I specifically would ask you provide

 

      that not in the ACS population, because the

 

      population that will be exposed to this if this

 

      drug comes to market that really is vulnerable that

 

      I'm concerned about is that non-ACS population.

 

                DR. SHETH:  Okay.

 

                DR. HIRSCH:  I don't want that to be a

 

                                                               128

 

      Band-aid for a potential adverse effect.

 

                DR. BORER:  Steve and then Bill.

 

                DR. NISSEN:  Just so you understand what

 

      we're concerned about--and several of us have made

 

      this observation--it is that because ximelagatran

 

      is a short-acting agent compared to Coumadin, our

 

      worry is that when you stop the drug, there's some

 

      phenomenon that goes on for a few days or a few

 

      weeks in which a patient has increased vulnerability and

 

      that that is the explanation for the

 

      excess cardiovascular events.  And we want to

 

      understand whether you have some response to that

 

      that we can factor into our thinking.

 

                DR. SHETH:  Can I ask, would it help the

 

      committee to take a look at other thrombotic events

 

      in terms of incident or rebound phenomena?  Because

 

      certainly patients who are usually at risk for

 

      venous events might typically get those kind of

 

      events.  Would that help--

 

                DR. NISSEN:  It only helps a little bit.

 

      The problem is that the pathophysiology of arterial

 

      and venous events are different.

 

                                                               129

 

                DR. SHETH:  Right.

 

                DR. NISSEN:  And so, you know, it appears

 

      that there is this excess of arterial thrombotic

 

      events post-treatment, and we're trying to

 

      understand that in order to factor that into the

 

      thinking here of the committee.

 

                DR. SHETH:  Right, although in maybe the

 

      treatment and prevention groups--

 

                DR. NISSEN:  Yes, yes.  I have another

 

      question, and forgive me for this, but I have to

 

      probe on something that I think is important.  If

 

      you could put up Slide No. CE-19, please?  I see

 

      these patients that are going to have knee

 

      replacement all the time in consultation.  They

 

      almost all get sent for cardiac clearance because

 

      they're older and they have a lot of cardiovascular

 

      risk factors, and I'll bet the other cardiologists

 

      at this table, like Jeff probably sees plenty of

 

      these as well.  And so when I see them, there are

 

      three things that I worry about.  I worry about, of

 

      course, them dying.  I worry about them having a

 

      pulmonary embolus.  And I worry about them having a

 

                                                               130

 

      myocardial infarction.

 

                And so, you know, to do the simple math

 

      here, which is what all of us are kind of looking

 

      at, if you look at the serious endpoints, the

 

      feared complications, what you see is--in EXULT A

 

      and B, you see three plus six is nine events with

 

      ximelagatran, and you see eight events here, PE or

 

      death, with warfarin.

 

                If you now put up Slide No.--

 

                DR. FLEMING:  Steve, just before you go,

 

      those nine and eight are 15 and 10 in the FDA

 

      briefing document.  It's worse than this.  It's 15

 

      and 10.

 

                DR. NISSEN:  Okay.  I'm trying to be--you

 

      know, not make this any more painful than it has to

 

      be.

 

                Now let's look at Slide CS-14, so we'll

 

      take nine and eight, so CS-14, and now I look at

 

      myocardial infarction, and it's 16 to 4.  And so

 

      when you put it together, you know, you see that

 

      the really serious events, the bad things that can

 

      happen to that patient I'm seeing in consultation

 

                                                               131

 

      look a lot worse on ximelagatran than warfarin.

 

      And so one has to ask the question:  Does it really

 

      look as good as it looks?

 

                And so what are your thoughts about this?

 

      I mean, MI is as bad an outcome as PE, isn't it?

 

                DR. SHETH:  Yes, it is.  In considering

 

      those numbers, I won't dispute how--the numbers

 

      that we just looked at, they are higher in the

 

      ximelagatran group compared to the warfarin group

 

      in the orthopedic surgery population.  The only

 

      comment I'd make is that, unfortunately--those are

 

      really small numbers, and the question is:  Is this

 

      a really--a true difference?  And I would

 

      anticipate that if it was a true effect that we

 

      would really see a significant effect in the

 

      long-term group just because it's so much larger.

 

                We also have another study that we started

 

      to do in extended prophylaxis in orthopedic

 

      surgery, so we'll be able to collect more data in

 

      that study as well.  But, again, the numbers are

 

      small so it's hard to know if this is a true

 

      difference or not.

 

                                                               132

 

                DR. NISSEN:  But, of course, the

 

      difference in the long-term studies is that this is

 

      one where you get the short-term administration,

 

      then you withdraw the drug, and so it speaks more

 

      to this question of an acute rebound sort of

 

      phenomenon.  I mean, I hope you can appreciate why

 

      it's something that really struck many of us on the

 

      committee as being a problem.

 

                DR. BORER:  It's also a potentially

 

      remediable problem, so it's important that you

 

      should know about it.

 

                Bill, and then Beverly.

 

                DR. HIATT:  Yes, just to follow up on

 

      that, it does seem like the surgical population may

 

      not be the same as the long-term treatment

 

      population, and the concept of risk

 

      occurring--excess risk occurring in that population

 

      is very real.

 

                Then the other question I have is, turning

 

      to the SPORTIF IV data, you didn't present that in

 

      any of your safety data.  Is that correct?

 

                DR. SHETH:  The SPORTIF II and IV data are

 

                                                               133

 

      actually pooled in the atrial fibrillation pool

 

      that we performed.  So it included that Phase II

 

      trial, yes.

 

                DR. HIATT:  If you look at page 97 of the

 

      briefing document, there are several phases to

 

      SPORTIF IV, and I count a total of 17 deaths on

 

      treatment versus warfarin is four.  So you're

 

      saying those deaths are included in the overall

 

      safety data you presented?

 

                DR. SHETH:  They are included, but I'll

 

      just point out that there are about 2 to 3 times

 

      more patients on--3 times more patients on

 

      ximelagatran than on warfarin in SPORTIF IV.  So

 

      they're not balanced groups.  The denominators are

 

      not balanced.

 

                DR. HIATT:  Correct.

 

                DR. SHETH:  But those deaths are included

 

      in the atrial fib pool and consequently in the

 

      long-term exposure pool.

 

                DR. HIATT:  Okay.

 

                DR. BORER:  Beverly, and then Dr. Sjogren.

 

                DR. LORELL:  To follow up on this concept

 

                                                               134

 

      of potential rebound--

 

                DR. SHETH:  Can you speak louder?

 

                DR. LORELL:  Yes, I can.  To follow up on

 

      the issues that were raised about potential rebound

 

      in the post-surgical population, can you enlighten

 

      us as to how investigators were instructed to use

 

      or no instructions on aspirin?  Was aspirin

 

      deliberately not used in that surgical population?

 

      And then were there any instructions at the

 

      termination of treatment?

 

                DR. SHETH:  Let me ask Dr. Berkowitz, who

 

      was the physician for those studies, to describe

 

      the use of aspirin instructions for the surgical

 

      population.

 

                DR. BERKOWITZ:  Scott Berkowitz,

 

      AstraZeneca.  I didn't get the second part.  The

 

      first part was that aspirin was precluded, kept to

 

      a minimum, and patients weren't to be on it

 

      routinely.

 

                DR. LORELL:  So I think the second part,

 

      was there a strategy in that trial when the study

 

      drug was stopped about reinstatement of aspirin in

 

                                                               135

 

      patients who had risk factors?  You know, the point

 

      that Dr. Borer made, this is a group with rich risk

 

      factors.

 

                DR. BERKOWITZ:  I'm sorry.  I think I got

 

      all your question.  The studies were designed to

 

      leave to the discretion of the investigators to put

 

      the patients back on the medicine, so we did not

 

      prespecify how to do that.

 

                DR. LORELL:  Okay.  And related to that,

 

      have you done any studies after withdrawal of the

 

      drug to look at what happens to platelet function?

 

                DR. BERKOWITZ:  In our clinical trials for

 

      VTE and orthopedic surgery and I believe in the

 

      atrial fibrillation trials, we did not do any

 

      platelet studies.

 

                DR. SHETH:  I can mention we actually

 

      looked and did an analysis of patients both on

 

      ximelagatran, on aspirin and off aspirin, for

 

      events in the atrial fibrillation pool.  If you're

 

      interested, we can show that if that would be

 

      helpful.  And this is not exactly the same as the

 

      patients who discontinued after orthopedic surgery.

 

                                                               136

 

      But if you're concerned about any increased

 

      beneficial effect--let's see.  Actually, what you

 

      see is that there is an incremental benefit in

 

      patients who are on aspirin, but you see that same

 

      benefit on warfarin, and you don't see a difference

 

      of the effect between the two anticoagulants when

 

      aspirin is added.

 

                DR. BORER:  The question that Beverly is

 

      asking, though, is what about after you've stopped

 

      the ximelagatran and the warfarin.  In that period,

 

      were people still on aspirin or were they not?  And

 

      did the fact that they were or weren't have any

 

      impact on the post-treatment events?

 

                DR. SHETH:  We didn't make specific

 

      recommendations after the trial.  They were to go

 

      on their regular medications per their physician.

 

                DR. BORER:  Okay.  Dr. Sjogren, then Alan,

 

      then Ron.

 

                DR. SJOGREN:  My question pertains to the

 

      potential hepatic toxicity, and I have a couple of

 

      questions.  One is you are proposing to follow up

 

      patients with ALTs, and then if they go over 2

 

                                                               137

 

      times the upper limit of normal, to follow up a

 

      little more closely and eventually discontinue the

 

      drug.  I'd like to know what kind of information do

 

      you have in the patients that you followed up that

 

      developed the ALT abnormality to back up that kind

 

      of recommendation.  That's one question.

 

                The second question is:  Do you have any

 

      information on patients with chronic liver disease

 

      that are treated with this medication?  What

 

      happens to them?

 

                And one request.  Do you have slides of

 

      the liver biopsy that was done that we can look at?

 

                DR. BORER:  Before you begin to answer,

 

      let me just state a rule here.  We're not asking

 

      you to tell us your algorithm for following

 

      patients.  Dr. Sjogren is just asking about the

 

      data that might be used to inform the development

 

      of such an algorithm and then the issue of the

 

      chronic use and the slides.

 

                DR. SHETH:  Okay.  Let me answer the

 

      latter two questions first, and I'm going to have

 

      to ask for a clarification on that first one.

 

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                We do not have a slide of the hepatic

 

      biopsy right now.  The chronic disease, because we

 

      identified early in the Phase II trial, SPORTIF II,

 

      that there was this asymptomatic transaminase

 

      increase, we actually excluded patients who had

 

      known hepatic disease from the trials, as well as

 

      patients who had an ALT above 2 times the upper

 

      limit of normal.  So that to the best of our

 

      knowledge, patients who--with the exception of the

 

      reactivation hepatitis B, should not have, in fact,

 

      been enrolled in the trial, and we would, in fact,

 

      propose a contraindication for those patients.  So

 

      we don't have data to understand the safety in that

 

      group.

 

                In terms of follow-up, are you asking

 

      me--you want to know what did we do to follow up

 

      all patients who had an elevation or what their

 

      outcome was?